U.S. patent number 9,090,586 [Application Number 13/813,786] was granted by the patent office on 2015-07-28 for heterocyclic compound.
This patent grant is currently assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED. The grantee listed for this patent is Makoto Fushimi, Tomoaki Hasui, Haruhi Kamisaki, Jun Kunitomo, Shinkichi Suzuki, Takahiko Taniguchi, Masato Yoshikawa. Invention is credited to Makoto Fushimi, Tomoaki Hasui, Haruhi Kamisaki, Jun Kunitomo, Shinkichi Suzuki, Takahiko Taniguchi, Masato Yoshikawa.
United States Patent |
9,090,586 |
Yoshikawa , et al. |
July 28, 2015 |
Heterocyclic compound
Abstract
The present invention provides a compound represented by the
formula (1): ##STR00001## wherein each symbol is as defined in the
specification, or a salt thereof, a prodrug of the compound or a
salt thereof, a medicament containing the compound or a salt
thereof, the medicament which is a phosphodiesterase 10A inhibitor,
and a medicament which is for preventing or treating
schizophrenia.
Inventors: |
Yoshikawa; Masato (Kanagawa,
JP), Suzuki; Shinkichi (Kanagawa, JP),
Hasui; Tomoaki (Kanagawa, JP), Fushimi; Makoto
(Kanagawa, JP), Kunitomo; Jun (Kanagawa,
JP), Kamisaki; Haruhi (Kanagawa, JP),
Taniguchi; Takahiko (Kanagawa, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Yoshikawa; Masato
Suzuki; Shinkichi
Hasui; Tomoaki
Fushimi; Makoto
Kunitomo; Jun
Kamisaki; Haruhi
Taniguchi; Takahiko |
Kanagawa
Kanagawa
Kanagawa
Kanagawa
Kanagawa
Kanagawa
Kanagawa |
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
JP
JP
JP
JP
JP
JP
JP |
|
|
Assignee: |
TAKEDA PHARMACEUTICAL COMPANY
LIMITED (Osaka, JP)
|
Family
ID: |
45559555 |
Appl.
No.: |
13/813,786 |
Filed: |
August 3, 2011 |
PCT
Filed: |
August 03, 2011 |
PCT No.: |
PCT/JP2011/067809 |
371(c)(1),(2),(4) Date: |
February 22, 2013 |
PCT
Pub. No.: |
WO2012/018059 |
PCT
Pub. Date: |
February 09, 2012 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20130150344 A1 |
Jun 13, 2013 |
|
Foreign Application Priority Data
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|
|
|
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Aug 4, 2010 [JP] |
|
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2010-175374 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/00 (20130101); C07D 413/14 (20130101); A61P
43/00 (20180101); C07D 403/04 (20130101); C07D
417/14 (20130101); A61P 25/14 (20180101); A61P
25/18 (20180101); C07D 401/14 (20130101); A61K
9/2059 (20130101); A61P 25/24 (20180101); A61P
25/22 (20180101); A61K 9/2018 (20130101); A61P
25/00 (20180101); A61P 25/28 (20180101); A61P
3/00 (20180101); A61P 3/04 (20180101); C07D
498/08 (20130101); A61P 25/32 (20180101); A61P
25/30 (20180101); C07D 403/14 (20130101); A61P
25/16 (20180101); A61P 25/36 (20180101); A61P
3/10 (20180101) |
Current International
Class: |
A61K
31/553 (20060101); C07D 417/14 (20060101); C07D
401/14 (20060101); A61K 9/00 (20060101); C07D
403/04 (20060101); A61K 9/20 (20060101); C07D
403/14 (20060101); A61K 31/525 (20060101); C07D
498/08 (20060101); C07D 413/14 (20060101); C07D
241/00 (20060101); C07D 413/00 (20060101); C07D
498/02 (20060101); C07D 401/00 (20060101); A61K
31/535 (20060101) |
Field of
Search: |
;514/211.15,252.05,230.5,236.5 ;544/238,105,114,230 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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8-511238 |
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Nov 1996 |
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JP |
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2010-510297 |
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Apr 2010 |
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JP |
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2010/063610 |
|
Jun 2010 |
|
WO |
|
2010/090737 |
|
Aug 2010 |
|
WO |
|
2012/018058 |
|
Feb 2012 |
|
WO |
|
2012/020780 |
|
Feb 2012 |
|
WO |
|
Other References
International Search Report issued Sep. 27, 2011 in International
(PCT) Application No. PCT/JP2011/067809. cited by applicant .
F. S. Menniti et al., "Phosphodiesterases in the CNS: Targets for
Drug Development", Nat. Rev. Drug Disc., vol. 5, pp. 660-670, Aug.
2006. cited by applicant .
M. D. Houslay et al., "cAMP-Specific Phosphodiesterase-4 Enzymes in
the Cardiovascular System: A Molecular Toolbox for Generating
Compartmentalized cAMP Signaling", Circulation Research, vol. 100,
No. 7, pp. 950-966, 2007. cited by applicant .
J. Nakayama et al., "Expression Cloning of a Human
.alpha.1,4-N-acetylglucosaminyltransferase that forms
GlcNAc.alpha.1.fwdarw.4Gal.beta..fwdarw.R, A Glycan Specifically
Expressed in the Gastric Gland Mucous Cell-Type Mucin", Proc. Natl.
Acad. Sci., vol. 96, pp. 8991-8996, Aug. 1999. cited by applicant
.
K. Fujishige et al., "Cloning and Characterization of a Novel Human
Phosphodiesterase that Hydrolyzes both cAMP and cGMP (PDE10A)", The
Journal of Biological Chemistry, vol. 274, No. 26, pp. 18438-18445,
1999. cited by applicant .
K. Loughney et al., "Isolation and Characterization of PDE10A, A
Novel Human 3', 5'-cyclic Nucleotide Phosphodiesterase", Gene, vol.
234, pp. 109-117, 1999. cited by applicant .
K. Fujishige et al., "Striatum- and Testis-Specific
Phosphodiesterase PDE10A Isolation and Characterization of a Rat
PDE10A", Eur. J. Biochem., vol. 266, pp. 1118-1127, 1999. cited by
applicant .
T. F. Seeger et al., "Immunohistochemical Localization of PDE10A in
the Rat Brain", Brain Research, vol. 985, pp. 113-126, 2003. cited
by applicant.
|
Primary Examiner: Murray; Jeffrey H
Assistant Examiner: Masha; Oluwafemi
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
L.L.P.
Claims
The invention claimed is:
1. A compound represented by formula (1) ##STR00140## wherein
R.sup.1 is an optionally substituted C.sub.1-6 alkoxy group,
R.sup.2 is a hydrogen atom or an optionally substituted C.sub.1-6
alkyl group, R.sup.3 is selected from the group consisting of the
following fused rings ##STR00141## wherein ring Aa is an optionally
substituted 5- or 6-membered heterocycle wherein the substituents
for ring Aa are optionally bonded to form a ring; and the benzene
ring or pyridine ring contained in the fused ring is optionally
substituted, or ##STR00142## wherein ring A.sup.b is a substituted
pyridine ring, an optionally substituted pyrazole ring, an
optionally substituted thiazole ring, an optionally substituted
pyrazine ring, an optionally substituted pyridazine ring, an
optionally substituted pyrimidine ring or an optionally substituted
imidazole ring, and R.sup.4 is an optionally substituted C.sub.1-6
alkyl group or an optionally substituted phenyl group, provided
that the following compounds: a compound wherein R.sup.1 is a
C.sub.1-6 alkoxy group substituted by substituent(s) having
optionally substituted cyclic group(s),
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(2,2,6-trifluoro-1,3-benzodioxol-
-5-yl)pyridazin-4(1H)-one, and
5-methoxy-1-(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-
-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one are excluded, or a salt
thereof.
2. The compound or salt of claim 1, wherein R.sup.3 is ##STR00143##
wherein R.sup.5 is a substituent, and Aa, the benzene ring and the
pyridine ring are as defined in claim 1.
3. The compound or salt of claim 2, wherein R.sup.5 is a halogen
atom or an optionally substituted C.sub.1-6 alkoxy group.
4. The compound or salt of claim 1, wherein R.sup.3 is ##STR00144##
wherein ring A.sup.b is a substituted pyridine ring or a
substituted pyrazole ring.
5.
5-{3-[1-(3-Chlorophenyl)-1H-pyrazol-5-yl]-5-methoxy-4-oxopyridazin-1(4-
H)-yl}-4-fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one or a
salt thereof.
6.
1-(Cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyraz-
ol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
or a salt thereof.
7.
1-[1-(1-Cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-py-
razol-5-yl)pyridazin-4(1H)-one or a salt thereof.
8.
5-Methoxy-1-[2-methoxy-6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-
-yl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt
thereof.
9.
1-[6-(3,4-difluoro-1H-pyrrol-1-yl)-2-methoxypyridin-3-yl]-5-methoxy-3--
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt
thereof.
10. A pharmaceutical composition comprising the compound or salt of
claim 1, and a pharmacologically acceptable carrier.
11. The pharmaceutical composition of claim 10, which is a
phosphodiesterase 10A inhibitor.
12. A method for treating schizophrenia which comprises
administering an effective amount of the compound or salt of claim
1 to a mammal.
Description
This application is a U.S. national stage of International
Application No. PCT/JP2011/067809 filed Aug. 3, 2011.
TECHNICAL FIELD
The present invention relates to a novel heterocyclic compound, a
production method thereof and a medicament containing same and the
like. More particularly, the present invention relates to a
compound having an inhibitory action on phosphodiesterase 10A and
effective as a prophylactic or therapeutic medicament for mental
diseases such as schizophrenia and the like, and the like.
BACKGROUND OF THE INVENTION
Phosphodiesterase (PDE) is an enzyme that hydrolyzes cAMP and cGMP
that function as intracellular second messengers into 5'-AMP and
5'-GMP, respectively. PDE gene is constituted with 21 genes, and
currently classified into 11 kinds of families based on the
molecular structure of the enzymes. Furthermore, each PDE is
classified into the following 3 kinds: 1) cAMP-PDEs (PDE4, PDE7,
PDE8), 2) cGMP-PDE (PDE5, PDE6, PDE9), and 3) dual-substrate PDEs
(PDE1, PDE2, PDE3, PDE10, PDE11), based on the substrate
specificity.
cAMP and cGMP are involved in the control of various physiological
functions such as control of ion channel, muscle relaxation,
learning and memory function, differentiation, apoptosis,
lipogenesis, glycogenolysis and gluconeogenesis. Particularly, they
are known to play an important role in the differentiation and
survival, as well as control of neurotransmission of the nerve cell
(non-patent document 1). Phosphorylation of various molecules that
control physiological functions such as transcription factors, ion
channel and receptor, which is caused by protein kinase A (PKA) and
protein kinase G (PKG), contributes to such control by cAMP and
cGMP, and the amounts of cAMP and cGMP in the cell are under
spatiotemporal regulation via generation by adenylate cyclase and
guanylate cyclase in response to extracellular stimulations and
degradation thereof by PDE (non-patent document 2). Since PDE is a
sole enzyme that decomposes cAMP and cGMP in vivo, PDE is
considered to play an important role in the regulation of cyclic
nucleotide signaling.
PDE10A is a molecule cloned and reported by 3 independent groups in
1999 (non-patent documents 3, 4). Expression analysis thereof has
elucidated that PDE10A shows high expression only in the brain and
testis, and has a localized expression pattern in the PDE family
(non-patent documents 5, 6). In the brain, both PDE10A mRNA and
PDE10A protein show high expression in medium spiny nerve cells of
the striatum (medium spiny neurons, MSNs) (non-patent documents 7,
8). MSNs are classified as two major kinds of pathways. One of them
is called a direct pathway or nigrostriatal pathway, and mainly
expresses dopamine D.sub.1 receptors. The other pathway, indirect
pathway, is called a striatum-globus pallidus pathway, and mainly
expresses dopamine D.sub.2 receptors. The direct pathway is
involved in the functions of motion execution and reward learning
and, on the other hand, the indirect pathway is involved in the
suppression of motility. The activity of the output nucleus of the
basal nucleus is regulated by the balance of antagonistic inputs
from these two kinds of pathways. Since PDE10A is expressed in MSNs
of both pathways, the both pathways are considered to be activated
by inhibition of PDE10A. Since the action of existing antipsychotic
agents having a D.sub.2 receptor shutting off action is mainly
mediated by the activation of indirect pathway, a PDE10A inhibitor
is expected to show an anti-mental disease action like existing
drugs.
The excess D.sub.2 receptor shutting off action in the brain by
existing drugs causes side effects such as hyperprolactinemia and
extrapyramidal syndrome. However, since PDE10A shows striatum
pathway specific expression and shows a lower expression level in
the pituitary gland mainly involved in the prolactin release,
PDE10A inhibitor is considered to have no prolactin concentration
increasing action in plasma. Moreover, since PDE10A is also
expressed in the direct pathway MSNs and activated by a PDE10A
inhibitor, it is considered to have superior characteristics than
existing antipsychotic agents that activate only indirect pathways.
That is, since the direct pathway is involved in the motion
execution, it is considered to antagonistically act against
extrapyramidal syndrome caused by excessive activation of indirect
pathway. Furthermore, this pathway is expected to show actions to
enhance the output from the striatum-thalamus circuit and promote
cognitive functions of reward learning and problem solving. Since
existing antipsychotic agents show a shutting off action on many
receptors, they pose problems of side effects such as body weight
increase and abnormal metabolism. PDE10A inhibitor is also
considered to be superior to the existing drugs in the side
effects, since it directly activates second messenger signaling
without receptor blocking action of dopamine and/or other
neurotransmitter. In view of the specific expression and its
function in the brain nerve system, PDE10A is considered to be
useful as a drug discovery target in neurological diseases, in
particular, psychotic disorders such as schizophrenia.
Patent document 1 discloses a compound of the following
formula:
##STR00002## and the following compounds:
##STR00003## as a PDE10A inhibitor.
Patent document 2 discloses a compound of the following
formula:
##STR00004## and the following compounds:
##STR00005## ##STR00006## as a PDE10A inhibitor.
DOCUMENT LIST
Patent Documents
Patent Document 1: WO 2010/063610 Patent Document 2: WO
2010/090737
Non-Patent Documents
Non-Patent Document 1: Nat. Rev. Drug Disc. 2006, vol. 5: 660
Non-Patent Document 2: Circ. Res. 2007, vol. 100(7): 950-966
Non-Patent Document 3: Proc. Natl. Acad. Sci. USA 1999, vol. 96:
8991-8996 Non-Patent Document 4: J. Biol. Chem. 1999, vol. 274:
18438-18445, Gene 1999, vol. 234: 109-117 Non-Patent Document 5:
Eur. J. Biochem. 1999, vol. 266: 1118-1127 Non-Patent Document 6:
J. Biol. Chem. 1999, vol. 274: 18438-18445 Non-Patent Document 7:
Eur. J. Biochem. 1999, vol. 266: 1118-1127 Non-Patent Document 8:
Brain Res. 2003, vol. 985: 113-126
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
The present invention aims to provide a compound having a PDE10A
inhibitory action and useful as a prophylactic or therapeutic drug
for mental diseases such as schizophrenia and the like.
Means of Solving the Problems
The present inventors discovered that a compound represented by the
formula (1) or a salt thereof (referred to as compound (1) in this
specification) has a PDE 10A inhibitory action and after extensive
investigation, completed the present invention.
In this specification, the compound (1) or a prodrug thereof is
also referred to the compound of the present invention.
Accordingly, the present invention provides
[1] a compound represented by the formula (1)
##STR00007## wherein R.sup.1 is an optionally substituted C.sub.1-6
alkoxy group, R.sup.2 is a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group, R.sup.3 is
##STR00008## wherein ring A.sup.a is an optionally substituted 5-
or 6-membered heterocycle wherein the substituents for ring A.sup.a
are optionally bonded to form a ring; and ring B.sup.a is an
optionally substituted benzene ring or an optionally substituted
pyridine ring, or
##STR00009## wherein ring A.sup.b is a substituted pyridine ring,
an optionally substituted pyrazole ring, an optionally substituted
thiazole ring, an optionally substituted pyrazine ring, an
optionally substituted pyridazine ring, an optionally substituted
pyrimidine ring or an optionally substituted imidazole ring, and
R.sup.4 is an optionally substituted C.sub.1-6 alkyl group or an
optionally substituted phenyl group, provided that the following
compound: a compound wherein R.sup.1 is a C.sub.1-6 alkoxy group
substituted by substituent(s) having optionally substituted cyclic
group(s),
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(2,2,6-trifluoro-1,3-benzodioxol-
-5-yl)pyridazin-4(1H)-one, and
5-methoxy-1-(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-
-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one are excluded, or a salt
thereof; [2] the compound or salt of the above-mentioned [1],
wherein R.sup.3 is
##STR00010## wherein R.sup.5 is a substituent, and the other
symbols are defined as in the above-mentioned [1]; [3] the compound
or salt of the above-mentioned [2], wherein R.sup.5 is a halogen
atom or an optionally substituted C.sub.1-6 alkoxy group; [4] the
compound or salt of the above-mentioned [1], wherein R.sup.3 is
##STR00011## wherein ring A.sup.b is a substituted pyridine ring or
a substituted pyrazole ring; [5]
5-{3-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-5-methoxy-4-oxopyridazin-1(4H)--
yl}-4-fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one or a salt
thereof; [6]
1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyra-
zol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
or a salt thereof; [7]
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyraz-
ol-5-yl)pyridazin-4(1H)-one or a salt thereof; [8]
5-methoxy-1-[2-methoxy-6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-yl-
]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt
thereof; [9]
1-[6-(3,4-difluoro-1H-pyrrol-1-yl)-2-methoxypyridin-3-yl]-5-methoxy-3-(1--
phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt thereof; [10]
a medicament comprising the compound or salt of the above-mentioned
[1]; [11] the medicament of the above-mentioned [10], which is a
phosphodiesterase 10A inhibitor; [12] the medicament of the
above-mentioned [10], which is for preventing or treating
schizophrenia; [13] a method for preventing or treating
schizophrenia which comprises administering an effective amount of
the compound or salt of the above-mentioned [1] to mammal; [14] use
of the compound or salt of the above-mentioned [1] in the
manufacture of a medicament for preventing or treating
schizophrenia; [15] the compound or salt of the above-mentioned [1]
for preventing or treating schizophrenia; and the like.
Effect of the Invention
The compound of the present invention has a PDE 10A inhibitory
action and is useful as a prophylactic or therapeutic medicament
for schizophrenia, etc.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the suppressive action of the compound on
an MK-801-induced locomotor hyperactivity in mouse (Experimental
Example 2).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail below.
Unless otherwise specified, in this specification, examples of the
"halogen atom" include fluorine, chlorine, bromine and iodine.
Unless otherwise specified, in this specification, the phrase
"optionally halogenated" or the term "halogeno" means that one or
more (e.g., 1 to 5) halogen atoms can be present as
substituents.
Unless otherwise specified, in this specification, examples of the
"alkyl (group)" include C.sub.1-6 alkyl (group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkyl (group)" include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl and hexyl.
Unless otherwise specified, in this specification, the term
"optionally halogenated C.sub.1-6 alkyl (group)" means C.sub.1-6
alkyl (group) which can be substituted by halogen atom(s), and
examples thereof include trifluoromethyl, difluoromethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl and
2,2,3,3,3-pentafluoropropyl.
Unless otherwise specified, in this specification, examples of the
"alkenyl (group)" include C.sub.2-6 alkenyl (group).
Unless otherwise specified, in this specification, examples of the
"C.sub.2-6 alkenyl (group)" include vinyl, 1-propen-1-yl,
2-propen-1-yl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, and
5-hexen-1-yl.
Unless otherwise specified, in this specification, examples of the
"alkynyl (group)" include C.sub.2-6 alkynyl (group). Examples of
the "C.sub.2-6 alkynyl (group)" include ethynyl, 1-propyn-1-yl,
2-propyn-1-yl, 4-pentyn-1-yl and 5-hexyn-1-yl.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkyl-C.sub.2-6 alkynyl (group)" include
cyclopropylethynyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkyl (group)" include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryl (group)" include phenyl, 1-naphthyl, 2-naphthyl,
2-biphenylyl, 3-biphenylyl, 4-biphenylyl and 2-anthryl.
Unless otherwise specified, in this specification, examples of the
"C.sub.7-16 aralkyl (group)" include benzyl, phenethyl,
diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,
2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,
2-biphenylylmethyl, 3-biphenylylmethyl and 4-biphenylylmethyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryl-C.sub.2-6 alkenyl (group)" include styryl.
Unless otherwise specified, in this specification, examples of the
"carbocycle having 5 to 6 carbon atoms" include a C.sub.5-6
cycloalkane (e.g., cyclopentane, cyclohexane), a C.sub.5-6
cycloalkene (e.g., cyclopentene, cyclohexene), a C.sub.5-6
cycloalkadiene (e.g., cyclopentadiene, cyclohexadiene) and a
benzene ring.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-6 cycloalkane" include cyclopropane, cyclobutane,
cyclopentane and cyclohexane.
Unless otherwise specified, in this specification, examples of the
"5- or 6-membered heterocycle" include a 5- or 6-membered
heterocycle containing, besides carbon atoms, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
Unless otherwise specified, in this specification, examples of the
"5- or 6-membered heterocycle containing, besides carbon atoms, 1
to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and
an oxygen atom" include a pyrrolidine ring, a tetrahydrofuran ring,
a tetrahydrothiophene ring, a piperidine ring, a tetrahydropyran
ring, a morpholine ring, a thiomorpholine ring, a piperazine ring,
a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an
isoxazole ring, a thiazole ring, an isothiazole ring, an imidazole
ring, a pyrroline ring (e.g., 1-pyrroline ring, 2-pyrroline ring,
3-pyrroline ring), a pyrazole ring, a 1,2,3-oxadiazole ring, a
1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan ring, a
1,2,3-thiadiazole ring, a 1,2,4-thiadiazole ring, a
1,3,4-thiadiazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole
ring, a tetrazole ring, a pyridine ring, a pyridazine ring, a
pyrimidine ring, a pyrazine ring and a triazine ring.
Unless otherwise specified, in this specification, the
"heterocyclic group" (and the heterocyclic moiety in a substituent)
is a non-aromatic heterocyclic group or a heteroaryl group (i.e.,
an aromatic heterocyclic group), and examples thereof include a 3-
to 14-membered heterocyclic group having 1 to 5 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen atom.
The "heterocyclic group" can be monocyclic, bicyclic or
tricyclic.
Unless otherwise specified, in this specification, examples of the
"3- to 14-membered heterocyclic group" include a 3- to 14-membered
aromatic heterocyclic group having 1 to 5 hetero atoms selected
from a nitrogen atom, a sulfur atom and an oxygen atom such as
pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g.,
2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl
(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (e.g.,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (e.g.,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g.,
2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (e.g.,
3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (e.g.,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g.,
1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxadiazolyl (e.g.,
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), thiadiazolyl (e.g.,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridyl
(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g.,
3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, isoindolyl (e.g.,
1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl), indolyl (e.g.,
1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,
7-indolyl), benzo[b]furanyl (e.g., 2-benzo[b]furanyl,
3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl,
6-benzo[b]furanyl, 7-benzo[b]furanyl), benzo[c]furanyl (e.g.,
1-benzo[c]furanyl, 4-benzo[c]furanyl, 5-benzo[c]furanyl),
benzo[b]thienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl,
4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl,
7-benzo[b]thienyl), benzo[c]thienyl (e.g., 1-benzo[c]thienyl,
4-benzo[c]thienyl, 5-benzo[c]thienyl), indazolyl (e.g.,
1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl,
6-indazolyl, 7-indazolyl), benzimidazolyl (e.g., 1-benzimidazolyl,
2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl,
6-benzimidazolyl), 1,2-benzisoxazolyl (e.g., 1,2-benzisoxazol-3-yl,
1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl,
1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl), benzoxazolyl (e.g.,
2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl,
7-benzoxazolyl), 1,2-benzisothiazolyl (e.g.,
1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl,
1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl,
1,2-benzisothiazol-7-yl), benzothiazolyl (e.g., 2-benzothiazolyl,
4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,
7-benzothiazolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl), quinolyl (e.g., 2-quinolyl,
3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), cinnolinyl (e.g.,
3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl,
7-cinnolinyl, 8-cinnolinyl), phthalazinyl (e.g., 1-phthalazinyl,
4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl,
8-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl,
4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,
8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl,
3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl,
8-quinoxalinyl), pyrazolo[1,5-a]pyridyl (e.g.,
pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,
pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl,
pyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-7-yl),
imidazo[1,2-a]pyridyl (e.g., imidazo[1,2-a]pyridin-2-yl,
imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,
imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl and
imidazo[1,2-a]pyridin-8-yl) and the like; and
a saturated or unsaturated 3- to 14-membered non-aromatic
heterocyclic group having 1 to 5 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom such as
tetrahydrofuryl, oxazolidinyl, imidazolinyl (e.g., 1-imidazolinyl,
2-imidazolinyl, 4-imidazolinyl), aziridinyl (e.g., 1-aziridinyl,
2-aziridinyl), azetidinyl (e.g., 1-azetidinyl, 2-azetidinyl),
pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl,
3-piperidinyl), azepanyl (e.g., 1-azepanyl, 2-azepanyl, 3-azepanyl,
4-azepanyl), azocanyl (e.g., 1-azocanyl, 2-azocanyl, 3-azocanyl,
4-azocanyl), piperazinyl (e.g., 1,4-piperazin-1-yl,
1,4-piperazin-2-yl), diazepinyl (e.g., 1,4-diazepin-1-yl,
1,4-diazepin-2-yl, 1,4-diazepin-5-yl, 1,4-diazepin-6-yl),
diazocanyl (e.g., 1,4-diazocan-1-yl, 1,4-diazocan-2-yl,
1,4-diazocan-5-yl, 1,4-diazocan-6-yl, 1,5-diazocan-1-yl,
1,5-diazocan-2-yl, 1,5-diazocan-3-yl), tetrahydropyranyl (e.g.,
tetrahydropyran-4-yl), morpholinyl (e.g., 4-morpholinyl),
thiomorpholinyl (e.g., 4-thiomorpholinyl), 2-oxazolidinyl,
dihydrofuryl, dihydropyranyl, dihydroindolyl (e.g.,
dihydroindol-5-yl), dihydroquinolyl and the like.
Unless otherwise specified, in this specification, examples of the
"aromatic heterocyclic group" (and the aromatic heterocyclic moiety
in a substituent) include the "3- to 14-membered aromatic
heterocyclic group having 1 to 5 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom" as exemplified
above as the above-mentioned "heterocyclic group".
Unless otherwise specified, in this specification, examples of the
"non-aromatic heterocyclic group" (and the aromatic heterocyclic
moiety in a substituent) include the "saturated or unsaturated 3-
to 14-membered non-aromatic heterocyclic group having 1 to 5 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom" as exemplified above as the above-mentioned "heterocyclic
group".
Unless otherwise specified, in this specification, examples of the
"saturated heterocyclic group" (and the saturated heterocyclic
moiety in a substituent) include those saturated group, from among
the above-mentioned "non-aromatic heterocyclic group". Specific
examples thereof include tetrahydrofuryl, morpholinyl,
thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and the
like.
Unless otherwise specified, in this specification, examples of the
"5- to 6-membered saturated heterocyclic group" (and the saturated
heterocyclic moiety in a substituent) include those having 5- to
6-membered group, from among the above-mentioned "saturated
heterocyclic group".
Unless otherwise specified, in this specification, examples of the
"alkoxy (group)" include C.sub.1-6 alkoxy (group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkoxy (group)" include methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy and
hexyloxy.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkyloxy (group)" include cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryloxy (group)" include phenyloxy, 1-naphthyloxy and
2-naphthyloxy.
Unless otherwise specified, in this specification, examples of the
"C.sub.7-16 aralkyloxy (group)" include benzyloxy and
phenethyloxy.
Unless otherwise specified, in this specification, examples of the
"alkyl-carbonyloxy (group)" include C.sub.1-6 alkyl-carbonyloxy
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkyl-carbonyloxy (group)" include acetoxy and
propionyloxy.
Unless otherwise specified, in this specification, examples of the
"alkoxy-carbonyloxy (group)" include C.sub.1-6 alkoxy-carbonyloxy
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkoxy-carbonyloxy (group)" include methoxycarbonyloxy,
ethoxycarbonyloxy, propoxycarbonyloxy and butoxycarbonyloxy.
Unless otherwise specified, in this specification, examples of the
"mono-alkyl-carbamoyloxy (group)" include mono-C.sub.1-6
alkyl-carbamoyloxy (group).
Unless otherwise specified, in this specification, examples of the
"mono-C.sub.1-6 alkyl-carbamoyloxy (group)" include
methylcarbamoyloxy and ethylcarbamoyloxy.
Unless otherwise specified, in this specification, examples of the
"di-alkyl-carbamoyloxy (group)" include di-C.sub.1-6
alkyl-carbamoyloxy (group).
Unless otherwise specified, in this specification, examples of the
"di-C.sub.1-6 alkyl-carbamoyloxy (group)" include
dimethylcarbamoyloxy and diethylcarbamoyloxy.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryl-carbonyloxy (group)" include benzoyloxy and
naphthylcarbonyloxy.
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.6-14 aryl-carbamoyloxy (group)" include
phenylcarbamoyloxy and naphthylcarbamoyloxy.
Unless otherwise specified, in this specification, examples of the
heterocyclic moiety of the "heterocyclyl-oxy (group)" include those
similar to the above-mentioned "heterocyclic group". Specific
examples of the "heterocyclyl-oxy (group)" include 5- to
14-membered heterocyclyl-oxy (group) having 1 to 5 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
Unless otherwise specified, in this specification, examples of the
aromatic heterocyclic moiety of the "aromatic heterocyclyl-oxy
(group)" include those similar to the "aromatic heterocyclic group"
as examples of the above-mentioned "heterocyclic group". Specific
examples of the "aromatic heterocyclyl-oxy (group)" include 3- to
14-membered aromatic heterocyclyl-oxy (group) having 1 to 5 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkylsulfonyloxy (group)" include methylsulfonyloxy and
ethylsulfonyloxy.
Unless otherwise specified, in this specification, examples of the
"halogeno C.sub.1-6 alkylsulfonyloxy (group)" include
halogenomethylsulfonyloxy and halogenoethylsulfonyloxy.
Unless otherwise specified, in this specification, examples of the
"alkylsulfanyl (group)" include C.sub.1-6 alkylsulfanyl
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkylsulfanyl (group)" include methylsulfanyl,
ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl,
sec-butylsulfanyl and tert-butylsulfanyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkylsulfanyl (group)" include cyclopropylsulfanyl,
cyclobutylsulfanyl, cyclopentylsulfanyl and cyclohexylsulfanyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 arylsulfanyl (group)" include phenylsulfanyl,
1-naphthylsulfanyl and 2-naphthylsulfanyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.7-16 aralkylsulfanyl (group)" include benzylsufanyl and
phenethylsulfanyl.
Unless otherwise specified, in this specification, examples of the
heterocyclic moiety of the "heterocyclyl-sulfanyl (group)" include
those similar to the above-mentioned "heterocyclic group". Specific
examples of the "heterocyclyl-sulfanyl (group)" include 5- to
14-membered heterocyclyl-sulfanyl (group) having 1 to 5 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
Unless otherwise specified, in this specification, examples of the
"alkyl-carbonyl (group)" include C.sub.1-6 alkyl-carbonyl
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkyl-carbonyl (group)" include acetyl, propionyl and
pivaloyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkyl-carbonyl (group)" include
cyclopropylcarbonyl, cyclopentylcarbonyl and
cyclohexylcarbonyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryl-carbonyl (group)" include benzoyl, 1-naphthoyl and
2-naphthoyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.7-16 aralkyl-carbonyl (group)" include phenylacetyl and
3-phenylpropionyl.
Unless otherwise specified, in this specification, examples of the
heterocyclic moiety of the "heterocyclyl-carbonyl (group)" include
those similar to the above-mentioned "heterocyclic group". Specific
examples thereof include 3- to 14-membered heterocyclyl-carbonyl
(group) having 1 to 5 hetero atoms selected from a nitrogen atom, a
sulfur atom and an oxygen atom. More specific examples thereof
include picolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl,
3-thenoyl, 2-furoyl, 3-furoyl, 4-morpholinylcarbonyl,
4-thiomorpholinylcarbonyl, aziridin-1-ylcarbonyl,
aziridin-2-ylcarbonyl, azetidin-1-ylcarbonyl,
azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl,
pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl,
piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl,
piperidin-3-ylcarbonyl, azepan-1-ylcarbonyl, azepan-2-ylcarbonyl,
azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcarbonyl,
azocan-2-ylcarbonyl, azocan-3-ylcarbonyl, azocan-4-ylcarbonyl,
1,4-piperazin-1-ylcarbonyl, 1,4-piperazin-2-ylcarbonyl,
1,4-diazepan-1-ylcarbonyl, 1,4-diazepan-2-ylcarbonyl,
1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl,
1,4-diazocan-1-ylcarbonyl, 1,4-diazocan-2-ylcarbonyl,
1,4-diazocan-5-ylcarbonyl, 1,4-diazocan-6-ylcarbonyl,
1,5-diazocan-1-ylcarbonyl, 1,5-diazocan-2-ylcarbonyl and
1,5-diazocan-3-ylcarbonyl.
Unless otherwise specified, in this specification, examples of the
"optionally esterified carboxy (group)" include carboxy, optionally
substituted alkoxy-carbonyl (group), optionally substituted
C.sub.6-14 aryloxy-carbonyl (group), optionally substituted
C.sub.7-16 aralkyloxy-carbonyl (group), optionally substituted
silyloxy-carbonyl (group) (e.g., TMS-O--CO--, TES-O--CO--,
TBS-O--CO--, TIPS-O--CO--, TBDPS-O--CO--) and the like.
Unless otherwise specified, in this specification, examples of the
"alkoxy-carbonyl (group)" include "C.sub.1-6 alkoxy-carbonyl
(group)".
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkoxy-carbonyl (group)" include methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryloxy-carbonyl (group)" include phenoxycarbonyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.7-16 aralkyloxy-carbonyl (group)" include benzyloxycarbonyl
and phenethyloxycarbonyl.
Unless otherwise specified, in this specification, examples of the
"alkylsulfonyl (group)" include C.sub.1-6 alkylsulfonyl
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkylsulfonyl (group)" include methylsulfonyl and
ethylsulfonyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkylsulfonyl (group)" include cyclopropylsulfonyl,
cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 arylsulfonyl (group)" include phenylsulfonyl,
1-naphthylsulfonyl and 2-naphthylsulfonyl.
Unless otherwise specified, in this specification, examples of the
heterocyclic moiety of the "heterocyclyl-sulfonyl (group)" include
those similar to the above-mentioned "heterocyclic group". Specific
examples of the "heterocyclyl-sulfonyl (group)" include 5- to
14-membered heterocyclyl-sulfonyl (group) having 1 to 5 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
Unless otherwise specified, in this specification, examples of the
"alkylsulfinyl (group)" include C.sub.1-6 alkylsulfinyl
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkylsulfinyl (group)" include methylsulfinyl and
ethylsulfinyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkylsulfinyl (group)" include cyclopropylsulfinyl,
cyclobutylsulfinyl, cyclopentylsufinyl and cyclohexysulfinyl.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 arylsulfinyl (group)" include phenylsulfinyl,
1-naphthylsulfinyl and 2-naphthylsulfinyl.
Unless otherwise specified, in this specification, examples of the
heterocyclic moiety of the "heterocyclyl-sulfinyl (group)" include
those similar to the above-mentioned "heterocyclic group". Specific
examples of the "heterocyclyl-sulfinyl (group)" include 5- to
14-membered heterocyclyl-sulfinyl (group) having. 1 to 5 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
Unless otherwise specified, in this specification, examples of the
"optionally substituted carbamoyl (group)" include carbamoyl
(group), optionally substituted mono- or di-alkyl-carbamoyl
(group).
Unless otherwise specified, in this specification, examples of the
"alkyl-carbamoyl (group)" include mono- or di-C.sub.1-6
alkyl-carbamoyl (group).
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.1-6 alkyl-carbamoyl (group)" include
methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,
dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl.
Unless otherwise specified, in this specification, examples of the
"mono- or di-alkylamino (group)" include mono- or di-C.sub.1-6
alkylamino (group)".
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.1-6 alkylamino (group)" include methylamino,
ethylamino, propylamino, dimethylamino and diethylamino.
Unless otherwise specified, in this specification, examples of the
"alkyl-carbonylamino (group)" include C.sub.1-6 alkyl-carbonylamino
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkyl-carbonylamino (group)" include acetylamino,
propionylamino and pivaloylamino.
Unless otherwise specified, in this specification, as the
heterocyclic moiety of the "heterocyclyl-amino (group)", for
example, those similar to the above-mentioned "heterocyclic group"
can be used. Examples of the "heterocyclyl-amino (group)" include
2-pyridyl-amino.
Unless otherwise specified, in this specification, as the
heterocyclic moiety of the "heterocyclyl-carbonylamino (group)",
those similar to the above-mentioned "heterocyclyl-carbonyl" can be
used. Examples of the "heterocyclyl-carbonylamino (group)" include
2-pyridyl-carbonylamino.
Unless otherwise specified, in this specification, as the
heterocyclic moiety of the "heterocyclyl-oxycarbonylamino (group)",
those similar to the above-mentioned "heterocyclic group" can be
used. Examples of the "heterocyclyl-oxycarbonylamino (group)"
include 2-pyridyl-oxycarbonylamino.
Unless otherwise specified, in this specification, as the
heterocyclic moiety of the "heterocyclyl-sulfonylamino (group)",
for example, those similar to the above-mentioned "heterocyclic
group" can be used. Examples of the "heterocyclyl-sulfonylamino
(group)" include 2-pyridyl-sulfonylamino.
Unless otherwise specified, in this specification, examples of the
"alkoxy-carbonylamino (group)" include C.sub.1-6
alkoxy-carbonylamino (group).
Unless otherwise specified, in this specification, the "C.sub.1-6
alkoxy-carbonylamino (group)" include methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino and
butoxycarbonylamino.
Unless otherwise specified, in this specification, examples of the
"alkylsulfonylamino (group)" include C.sub.1-6 alkylsulfonylamino
(group).
Unless otherwise specified, in this specification, examples of the
"C.sub.1-6 alkylsulfonylamino (group)" include methylsulfonylamino
and ethylsulfonylamino.
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.3-7 cycloalkylamino (group)" include
cyclopropylamino, cyclopentylamino and cyclohexylamino.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkyl-carbonylamino (group)" include
cyclopropylcarbonylamino, cyclopentylcarbonylamino and
cyclohexylcarbonylamino.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkyloxy-carbonylamino (group)" include
cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino and
cyclohexyloxycarbonylamino.
Unless otherwise specified, in this specification, examples of the
"C.sub.3-7 cycloalkylsulfonylamino (group)" include
cyclopropylsulfonylamino, cyclopentylsulfonylamino and
cyclohexylsulfonylamino.
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.6-14 arylamino (group)" include phenylamino and
diphenylamino.
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.7-16 aralkylamino (group)" include
benzylamino.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 aryl-carbonylamino (group)" include benzoylamino and
naphthoylamino.
Unless otherwise specified, in this specification, examples of the
"C.sub.6-14 arylsulfonylamino (group)" include phenylsulfonylamino,
2-naphthylsulfonylamino and 1-naphthylsulfonylamino.
Unless otherwise specified, in this specification, examples of the
"optionally substituted carbamoylamino (group)" include
carbamoylamino (group), optionally substituted mono- or
di-alkyl-carbamoylamino (group).
Unless otherwise specified, in this specification, examples of the
"mono- or di-alkyl-carbamoylamino (group)" include mono- or
di-C.sub.1-6 alkyl-carbamoylamino (group).
Unless otherwise specified, in this specification, examples of the
"mono- or di-C.sub.1-6 alkyl-carbamoylamino (group)" include
methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino,
dimethylcarbamoylamino, diethylcarbamoylamino and
ethylmethylcarbamoylamino.
[Substituent Group A]
In the present specification, Substituent Group A consists of
(1) a halogen atom;
(2) a nitro group;
(3) a cyano group;
(4) an optionally esterified carboxy group;
[e.g., a carboxy group,
an optionally substituted alkoxy-carbonyl group,
an optionally substituted C.sub.6-14 aryloxy-carbonyl group,
an optionally substituted C.sub.7-16 aralkyloxy-carbonyl group,
an optionally substituted silyloxy-carbonyl group and the
like];
(5) an optionally substituted alkyl group;
(6) an optionally substituted alkenyl group;
(7) an optionally substituted alkynyl group
(8) an optionally substituted C.sub.3-7 cycloalkyl-C.sub.2-6
alkynyl group;
(9) an optionally substituted C.sub.3-7 cycloalkyl group;
(10) an optionally substituted C.sub.6-14 aryl group;
(11) an optionally substituted C.sub.7-16 aralkyl group;
(12) an optionally substituted C.sub.6-14 aryl-C.sub.2-6 alkenyl
group;
(13) an optionally substituted heterocyclic group;
(14) a hydroxy group;
(15) an optionally substituted alkoxy group;
(16) an optionally substituted C.sub.3-7 cycloalkyloxy group;
(17) an optionally substituted C.sub.6-14 aryloxy group;
(18) an optionally substituted C.sub.7-16 aralkyloxy group;
(19) an optionally substituted alkyl-carbonyloxy group;
(20) an optionally substituted alkoxy-carbonyloxy group;
(21) an optionally substituted mono-alkyl-carbamoyloxy group;
(22) an optionally substituted di-alkyl-carbamoyloxy group;
(23) an optionally substituted C.sub.6-14 aryl-carbonyloxy
group;
(24) an optionally substituted mono- or di-C.sub.6-14
aryl-carbamoyloxy group;
(25) an optionally substituted heterocyclyl-oxy group (e.g., an
optionally substituted aromatic heterocyclyl-oxy group);
(26) an optionally substituted C.sub.1-6 alkylsulfonyloxy group
(e.g., an optionally substituted halogeno C.sub.1-6
alkylsulfonyloxy group),
(27) a mercapto group;
(28) an optionally substituted alkylsulfanyl group;
(29) an optionally substituted C.sub.3-7 cycloalkylsulfanyl
group;
(30) an optionally substituted C.sub.6-14 arylsulfanyl group;
(31) an optionally substituted C.sub.7-16 aralkylsulfanyl
group;
(32) an optionally substituted heterocyclyl-sulfanyl group;
(33) a formyl group;
(34) an optionally substituted alkyl-carbonyl group;
(35) an optionally substituted C.sub.3-7 cycloalkyl-carbonyl
group;
(36) an optionally substituted C.sub.6-14 aryl-carbonyl group;
(37) an optionally substituted C.sub.7-16 aralkyl-carbonyl
group;
(38) an optionally substituted heterocyclyl-carbonyl group;
(39) an optionally substituted alkylsulfonyl group;
(40) an optionally substituted C.sub.3-7 cycloalkylsulfonyl
group;
(41) an optionally substituted C.sub.6-14 arylsulfonyl group;
(42) an optionally substituted heterocyclyl-sulfonyl group;
(43) an optionally substituted alkylsulfinyl group;
(44) an optionally substituted C.sub.3-7 cycloalkylsulfinyl
group;
(45) an optionally substituted C.sub.6-14 arylsulfinyl group;
(46) an optionally substituted heterocyclyl-sulfinyl group;
(47) a sulfo group;
(48) a sulfamoyl group;
(49) a sulfinamoyl group;
(50) a sulfenamoyl group;
(51) a thiocarbamoyl group;
(52) an optionally substituted carbamoyl group [e.g., a carbamoyl
group, an optionally substituted mono- or di-alkyl-carbamoyl group
and the like];
(53) an optionally substituted amino group
[e.g.,
an amino group,
an optionally substituted mono- or di-alkylamino group,
an optionally substituted mono- or di-C.sub.3-7 cycloalkylamino
group,
an optionally substituted mono- or di-C.sub.6-14 arylamino
group,
an optionally substituted mono- or di-C.sub.7-16 aralkylamino
group,
an optionally substituted heterocyclyl-amino group,
an optionally substituted C.sub.6-14 aryl-carbonylamino group,
a formylamino group,
an optionally substituted alkyl-carbonylamino group (e.g., an
optionally substituted mono-(C.sub.1-6 alkyl-carbonyl)-amino
group),
an optionally substituted C.sub.3-7 cycloalkyl-carbonylamino
group,
an optionally substituted heterocyclyl-carbonylamino group,
an optionally substituted alkoxy-carbonylamino group,
an optionally substituted C.sub.3-7 cycloalkyloxy-carbonylamino
group,
an optionally substituted heterocyclyl-oxycarbonylamino group,
an optionally substituted carbamoylamino group [e.g., a
carbamoylamino group, an optionally substituted mono- or
di-C.sub.1-6 alkyl-carbamoylamino group and the like],
an optionally substituted alkylsulfonylamino group,
an optionally substituted C.sub.3-7 cycloalkylsulfonylamino
group,
an optionally substituted heterocyclyl-sulfonylamino group,
an optionally substituted C.sub.6-14 arylsulfonylamino group];
(54) an oxo group; and
(55) an oxido group.
The number of the substituents is preferably 0 (i.e.,
unsubstituted) or 1 to 5. It is more preferably 0 (i.e.,
unsubstituted).
Examples of the substituent of the
"optionally substituted alkoxy-carbonyl group",
"optionally substituted alkyl group",
"optionally substituted alkenyl group",
"optionally substituted alkynyl group",
"optionally substituted alkoxy group",
"optionally substituted alkyl-carbonyloxy group",
"optionally substituted alkoxy-carbonyloxy group",
"optionally substituted mono-alkyl-carbamoyloxy group",
"optionally substituted di-alkyl-carbamoyloxy group",
"optionally substituted C.sub.1-6 alkylsulfonyloxy group",
"optionally substituted halogeno C.sub.1-6 alkylsulfonyloxy
group",
"optionally substituted alkylsulfanyl group",
"optionally substituted alkyl-carbonyl group",
"optionally substituted alkylsulfonyl group",
"optionally substituted alkylsulfinyl group",
"optionally substituted mono- or di-alkyl-carbamoyl group",
"optionally substituted mono- or di-alkylamino group",
"optionally substituted alkyl-carbonylamino group",
"optionally substituted mono- or di-C.sub.1-6 alkyl-carbamoylamino
group",
"optionally substituted mono-(C.sub.1-6 alkyl-carbonyl)-amino
group",
"optionally substituted alkoxy-carbonylamino group",
"optionally substituted alkylsulfonylamino group", and
"optionally substituted silyloxy-carbonyl group" of the Substituent
Group A include those selected from the following Substituent Group
B.
Examples of the substituent of the
"optionally substituted C.sub.6-14 aryloxy-carbonyl group",
"optionally substituted C.sub.7-16 aralkyloxy-carbonyl group",
"optionally substituted C.sub.3-7 cycloalkyl-C.sub.2-6 alkynyl
group",
"optionally substituted C.sub.3-7 cycloalkyl group",
"optionally substituted C.sub.6-14 aryl group",
"optionally substituted C.sub.7-16 aralkyl group",
"optionally substituted C.sub.6-14 aryl-C.sub.2-6 alkenyl
group",
"optionally substituted heterocyclic group",
"optionally substituted C.sub.3-7 cycloalkyloxy group",
"optionally substituted C.sub.6-14 aryloxy group",
"optionally substituted C.sub.7-16 aralkyloxy group",
"optionally substituted C.sub.6-14 aryl-carbonyloxy group",
"optionally substituted mono- or di-C.sub.6-14 aryl-carbamoyloxy
group",
"optionally substituted heterocyclyl-oxy group",
"optionally substituted aromatic heterocyclyl-oxy group",
"optionally substituted C.sub.3-7 cycloalkylsulfanyl group",
"optionally substituted C.sub.6-14 arylsulfanyl group",
"optionally substituted C.sub.7-16 aralkylsulfanyl group",
"optionally substituted heterocyclyl-sulfanyl group",
"optionally substituted C.sub.3-7 cycloalkyl-carbonyl group",
"optionally substituted C.sub.6-14 aryl-carbonyl group",
"optionally substituted C.sub.7-16 aralkyl-carbonyl group",
"optionally substituted heterocyclyl-carbonyl group",
"optionally substituted C.sub.3-7 cycloalkylsulfonyl group",
"optionally substituted C.sub.6-14 arylsulfonyl group",
"optionally substituted heterocyclyl-sulfonyl group",
"optionally substituted C.sub.3-7 cycloalkylsulfinyl group",
"optionally substituted C.sub.6-14 arylsulfinyl group",
"optionally substituted heterocyclyl-sulfinyl group",
"optionally substituted mono- or di-C.sub.3-8 cycloalkylamino
group",
"optionally substituted mono- or di-C.sub.6-14 arylamino
group",
"optionally substituted mono- or di-C.sub.7-16 aralkylamino
group",
"optionally substituted heterocyclyl-amino group",
"optionally substituted C.sub.6-14 aryl-carbonylamino group",
"optionally substituted C.sub.3-7 cycloalkyl-carbonylamino
group",
"optionally substituted heterocyclyl-carbonylamino group",
"optionally substituted C.sub.3-7 cycloalkyloxy-carbonylamino
group",
"optionally substituted heterocyclyl-oxycarbonylamino group",
"optionally substituted C.sub.3-7 cycloalkylsulfonylamino
group",
"optionally substituted heterocyclyl-sulfonylamino group", and
"optionally substituted C.sub.6-14 arylsulfonylamino group" of the
Substituent Group A include those selected from the following
Substituent Group B and the following Substituent Group B'. The
number of the substituents is 1-substitutable maximum number, more
preferably 1-3, further preferably 1.
In the present specification, Substituent Group B consists of
(a) a halogen atom;
(b) a hydroxy group;
(c) a nitro group;
(d) a cyano group;
(e) an optionally substituted C.sub.6-14 aryl group (the C.sub.6-14
aryl group is optionally substituted by substituent(s) such as a
halogen atom, hydroxy, cyano, amino, optionally halogenated
C.sub.1-6 alkyl, mono- or di-C.sub.1-6 alkylamino, mono- or
di-C.sub.6-14 arylamino, mono- or di-C.sub.7-16 aralkylamino,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, formyl, C.sub.1-6
alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl, C.sub.6-14
aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl and the like); (f) an optionally substituted
C.sub.6-14 aryloxy group (the C.sub.6-14 aryloxy group is
optionally substituted by substituent(s) such as a halogen atom,
hydroxy, cyano, amino, optionally halogenated C.sub.1-6 alkyl,
mono- or di-C.sub.1-6 alkylamino, mono- or di-C.sub.6-14 arylamino,
mono- or di-C.sub.7-16 aralkylamino, C.sub.3-7 cycloalkyl,
C.sub.1-6 alkoxy, formyl, C.sub.1-6 alkyl-carbonyl, C.sub.3-7
cycloalkyl-carbonyl, C.sub.6-14 aryl-carbonyl, C.sub.7-16
aralkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-14
aryloxy-carbonyl, C.sub.7-16 aralkyloxy-carbonyl, C.sub.1-6
alkylsulfanyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl,
carbamoyl, thiocarbamoyl, mono- or di-C.sub.1-6 alkyl-carbamoyl,
mono- or di-C.sub.6-14 aryl-carbamoyl and the like); (g) an
optionally substituted C.sub.7-16 aralkyloxy group (the C.sub.7-16
aralkyloxy group is optionally substituted by substituent(s) such
as a halogen atom, hydroxy, cyano, amino, optionally halogenated
C.sub.1-6 alkyl, mono- or di-C.sub.1-6 alkylamino, mono- or
di-C.sub.6-14 arylamino, mono- or di-C.sub.7-16 aralkylamino,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, formyl, C.sub.1-6
alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl, C.sub.6-14
aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl and the like); (h) an optionally substituted 5- to
10-membered heterocyclic group having 1 to 4 hetero atoms selected
from a nitrogen atom, a sulfur atom and an oxygen atom (e.g.,
furyl, pyridyl, thienyl, pyrrolidino, 1-piperidinyl, 4-piperidyl,
piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, azepan-1-yl,
azocan-1-yl, azonan-1-yl, 3,4-dihydroisoquinolin-2-yl and the like)
(the heterocyclic group is optionally substituted by substituent(s)
such as a halogen atom, hydroxy, cyano, amino, optionally
halogenated C.sub.1-6 alkyl, mono- or di-C.sub.1-6 alkylamino,
mono- or di-C.sub.6-14 arylamino, mono- or di-C.sub.7-16
aralkylamino, C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, formyl,
C.sub.1-6 alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl, C.sub.6-14
aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl and the like); (i) an optionally substituted amino
group [for example, an amino group optionally substituted by 1 or 2
substituents selected from the group consisting of C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.6-14 aryl, C.sub.7-16 aralkyl, a
heterocyclic group and heterocyclyl-alkyl (the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.6-14 aryl, C.sub.7-16 aralkyl, a
heterocyclic group and heterocyclyl-alkyl are each optionally
substituted by substituent(s) such as a halogen atom, hydroxy,
cyano, amino, optionally halogenated C.sub.1-6 alkyl (which is not
a substituent for alkyl and alkenyl), mono- or di-C.sub.1-6
alkylamino, mono- or di-C.sub.6-14 arylamino, mono- or
di-C.sub.7-16 aralkylamino, C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy,
formyl, C.sub.1-6 alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl,
C.sub.6-14 aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.3-7 cycloalkyloxy-carbonyl, C.sub.6-14
aryloxy-carbonyl, C.sub.7-16 aralkyloxy-carbonyl, C.sub.1-6
alkylsulfanyl, C.sub.3-7 cycloalkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.3-7 cycloalkylsulfinyl, C.sub.1-6
alkylsulfonyl, C.sub.3-7 cycloalkylsulfonyl, carbamoyl,
thiocarbamoyl, mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or
di-C.sub.6-14 aryl-carbamoyl and the like, and examples of the
"heterocyclic group" and "heterocyclyl-" of the
"heterocyclyl-alkyl" include those similar to the above-mentioned
"heterocyclic group".)]; (j) C.sub.3-7 cycloalkyl; (k) an
optionally substituted C.sub.1-6 alkoxy group (the C.sub.1-6 alkoxy
group is optionally substituted by substituent(s) such as a halogen
atom, hydroxy, amino, mono- or di-C.sub.1-6 alkylamino, mono- or
di-C.sub.6-14 arylamino, C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy,
formyl, C.sub.1-6 alkyl-carbonyl, C.sub.3-7 Cycloalkyl-carbonyl,
C.sub.6-14 aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl, trimethylsilyl (TMS) and the like); (l) a formyl
group; (m) a C.sub.1-6 alkyl-carbonyl group (e.g., acetyl); (n) a
C.sub.3-7 cycloalkyl-carbonyl group; (o) a C.sub.6-14 aryl-carbonyl
group; (p) a C.sub.7-16 aralkyl-carbonyl group; (q) a C.sub.1-6
alkoxy-carbonyl group; (r) a C.sub.6-14 aryloxy-carbonyl group; (s)
a C.sub.7-16 aralkyloxy-carbonyl group; (t) a C.sub.1-6
alkylsulfanyl group; (u) a C.sub.1-6 alkylsulfinyl group; (v) a
C.sub.1-6 alkylsulfonyl group; (w) a carbamoyl group; (x) a
thiocarbamoyl group; (y) a mono-C.sub.1-6 alkyl-carbamoyl group
(e.g., methylcarbamoyl, ethylcarbamoyl and the like); (z) a
di-C.sub.1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl,
diethylcarbamoyl, ethylmethylcarbamoyl and the like); (aa) a mono-
or di-C.sub.6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl,
1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like); (bb) a
mono- or di-5- to 7-membered heterocyclyl-carbamoyl group having 1
to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and
an oxygen atom (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,
4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the
like); and (cc) an oxo group.
In the present specification, Substituent Group B' consists of
(a) an optionally substituted C.sub.1-6 alkyl group (the C.sub.1-6
alkyl group is optionally substituted by substituent(s) such as a
halogen atom, hydroxy, cyano, amino, mono- or di-C.sub.1-6
alkylamino, mono- or di-C.sub.6-14 arylamino, mono- or
di-C.sub.7-16 aralkylamino, C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy,
formyl, C.sub.1-6 alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl,
C.sub.6-14 aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl and the like); (b) an optionally substituted
C.sub.2-6 alkenyl group (the C.sub.2-6 alkenyl group is optionally
substituted by substituent(s) such as a halogen atom, hydroxy,
cyano, amino, mono- or di-C.sub.1-6 alkylamino, mono- or
di-C.sub.6-14 arylamino, mono- or di-C.sub.7-16 aralkylamino,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, formyl, C.sub.1-6
alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl, C.sub.6-14
aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl and the like); and (c) an optionally substituted
C.sub.2-6 alkynyl group (the C.sub.2-6 alkynyl group is optionally
substituted by substituent(s) such as a halogen atom, hydroxy,
cyano, amino, mono- or di-C.sub.1-6 alkylamino, mono- or
di-C.sub.6-14 arylamino, mono- or di-C.sub.7-16 aralkylamino,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, formyl, C.sub.1-6
alkyl-carbonyl, C.sub.3-7 cycloalkyl-carbonyl, C.sub.6-14
aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, C.sub.1-6 alkylsulfanyl, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl,
mono- or di-C.sub.1-6 alkyl-carbamoyl, mono- or di-C.sub.6-14
aryl-carbamoyl and the like).
The symbols in the following formula (1) are explained below.
R.sup.1 is an optionally substituted C.sub.1-6 alkoxy group.
Examples of the substituent of the "optionally substituted
C.sub.1-6 alkoxy group" for R.sup.1 include substituents selected
from the above-mentioned Substituent Group B. The number of the
substituents is preferably 0, or 1 or more, more preferably 0 or 1
to 5. The substituent is not a "substituent having optionally
substituted cyclic group(s)".
R.sup.1 is preferably a C.sub.1-6 alkoxy group, particularly
preferably a methoxy group.
R.sup.2 is a hydrogen atom or an optionally substituted C.sub.1-6
alkyl group. Examples of the substituent of the "optionally
substituted C.sub.1-6 alkyl group" for R.sup.2 include substituents
selected from the above-mentioned Substituent Group B. The number
of the substituents is preferably 0, or 1 or more, more preferably
0 or 1 to 5.
R.sup.2 is preferably a hydrogen atom or a C.sub.1-6 alkyl group,
particularly preferably a hydrogen atom or a methyl group.
R.sup.3 is
##STR00012## wherein ring A.sup.a is an optionally substituted 5-
or 6-membered heterocycle wherein the substituents for ring A.sup.a
are optionally bonded to form a ring; and ring B.sup.a is an
optionally substituted benzene ring or an optionally substituted
pyridine ring, or
##STR00013## wherein ring A.sup.b is a substituted pyridine ring,
an optionally substituted pyrazole ring, an optionally substituted
thiazole ring, an optionally substituted pyrazine ring, an
optionally substituted pyridazine ring, an optionally substituted
pyrimidine ring or an optionally substituted imidazole ring.
Each symbol in R.sup.3 is explained below.
In the formula:
##STR00014## ring A.sup.a is an optionally substituted 5- or
6-membered heterocycle; and ring B.sup.a is an optionally
substituted benzene ring or an optionally substituted pyridine
ring.
In this case, R.sup.3 contains any group represented by the
following formula.
##STR00015##
Examples of the "5- or 6-membered heterocycle" of the "optionally
substituted 5- or 6-membered heterocycle" for ring A.sup.a include
a "5- or 6-membered heterocycle containing, besides carbon atoms, 1
to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and
an oxygen atom", from among the above-exemplified "5- or 6-membered
heterocycle". Examples of the "5- or 6-membered heterocycle"
include a pyrrolidine ring, a tetrahydrofuran ring, a
tetrahydrothiophene ring, a piperidine ring, a tetrahydropyran
ring, a morpholine ring, a thiomorpholine ring, a piperazine ring,
a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an
isoxazole ring, a thiazole ring, an isothiazole ring, an imidazole
ring, a pyrroline ring (e.g., a 1-pyrroline ring, a 2-pyrroline
ring, a 3-pyrroline ring), a pyrazole ring, a 1,2,3-oxadiazole
ring, a furazan ring, a 1,2,3-thiadiazole ring, a 1,2,3-triazole
ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a
pyrazine ring, a triazine ring and the like. Among them, a
2-pyrroline ring, an imidazole ring and the like are
preferable.
Examples of the substituent of the "optionally substituted 5- or
6-membered heterocycle" for ring A.sup.a include substituents
selected from the above-mentioned Substituent Group A.
Among them, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted C.sub.3-7 cycloalkyl group, an oxo group and
the like are preferable, and
a C.sub.1-6 alkyl group optionally substituted by substituent(s)
selected from a halogen atom and a C.sub.3-7 cycloalkyl group, a
C.sub.3-7 cycloalkyl group, an oxo group and the like are more
preferable.
The substituents for ring A.sup.a are optionally bonded to form a
ring. Examples of the ring include a C.sub.3-6 cycloalkane and the
like formed by the substituents for ring A.sup.a, in combination,
together with the carbon atoms which are ring constituting atoms of
ring A.sup.a. Preferably, the substituents for ring A.sup.a form a
spiro ring with a C.sub.3-6 cycloalkane.
The number of the substituents of the "optionally substituted 5- or
6-membered heterocycle" for ring A.sup.a is preferably 0, or 1 or
more, more preferably 1 to 4, further preferably 3 to 4.
Examples of the substituent of the "optionally substituted benzene
ring" for ring B.sup.a include substituents selected from the
above-mentioned Substituent Group A. Among them, a halogen atom is
preferable.
The number of the substituents of the "optionally substituted
benzene ring" for ring B.sup.a is preferably 0, or 1 or more, more
preferably 1 to 3, further preferably 1.
Examples of the substituent of the "optionally substituted pyridine
ring" for ring B.sup.a include substituents selected from the
above-mentioned Substituent Group A.
The number of the substituents of the "optionally substituted
pyridine ring" for ring B.sup.a is preferably 0, or 1 or more, more
preferably 0, 1 or 2.
In the formula:
##STR00016## at least one of the two ring-constituting atoms of
ring A.sup.a which are adjacent to the two carbon atoms which ring
A.sup.a and ring B.sup.a have in common is preferably an atom other
than an oxygen atom. That is, the formula:
##STR00017## is preferably not the formula:
##STR00018## wherein ring A.sup.a1 is an optionally substituted 5-
or 6-membered heterocycle.
In another embodiment, the formula:
##STR00019## is preferably a group represented by
##STR00020##
wherein
R.sup.5 is a substituent, and
the other symbols are defined as in the above-mentioned [1].
Examples of the "substituent" for R.sup.5 include substituents
selected from the above-mentioned Substituent Group A.
R.sup.5 is preferably a halogen atom or an optionally substituted
C.sub.1-6 alkoxy group, more preferably a halogen atom (e.g., a
fluorine atom).
In another embodiment,
the formula:
##STR00021## is preferably a group represented by
##STR00022## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); R.sup.a and R.sup.b are the same or different and
each is a C.sub.1-6 alkyl group, or R.sup.a and R.sup.b in
combination form a C.sub.3-6 cycloalkane; and R.sup.c is a
C.sub.1-6 alkyl group optionally substituted by substituent(s)
selected from a halogen atom and a C.sub.3-7 cycloalkyl group, or a
C.sub.3-7 cycloalkyl group, or a group represented by
##STR00023## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); and R.sup.d and R.sup.e are the same or different
and each is a C.sub.1-6 alkyl group.
The number of the halogen atoms of the above-mentioned "benzene
ring substituted by halogen atom(s)" is preferably 1 to 3, more
preferably 1.
In the formula:
##STR00024## ring A.sup.b is a substituted pyridine ring, an
optionally substituted pyrazole ring, an optionally substituted
thiazole ring, an optionally substituted pyrazine ring, an
optionally substituted pyridazine ring, an optionally substituted
pyrimidine ring or an optionally substituted imidazole ring.
Examples of the substituent of the "substituted pyridine ring" for
ring A.sup.b include substituents selected from the above-mentioned
Substituent Group A. Among them, an oxido group, a C.sub.1-6 alkoxy
group, a pyrrolidinyl group substituted by halogen atom(s), a
pyrrolyl group substituted by halogen atom(s) and the like are
preferable.
The number of the substituents of the "substituted pyridine ring"
for ring A.sup.b is preferably 1 or more, more preferably 1 to 3,
particularly preferably 1 or 2.
Examples of the substituent of the "optionally substituted pyrazole
ring" for ring A.sup.b include substituents selected from the
above-mentioned Substituent Group A. Among them, an optionally
substituted C.sub.1-6 alkyl and the like are preferable, and a
C.sub.1-6 alkyl group substituted by substituent(s) selected from a
halogen atom, a C.sub.3-7 cycloalkyl group optionally substituted
by C.sub.1-6 alkyl group(s) and a phenyl group, and the like are
more preferable.
The number of the substituents of the "optionally substituted
pyrazole ring" for ring A.sup.b is preferably 0, or 1 or more, more
preferably 1 to 3, particularly preferably 1 or 2.
Examples of the substituent of the "optionally substituted thiazole
ring", "optionally substituted pyrazine ring", "optionally
substituted pyridazine ring", "optionally substituted pyrimidine
ring" and "optionally substituted imidazole ring" for ring A.sup.b
include substituents selected from the above-mentioned Substituent
Group A. The number of the substituents is preferably 0, or 1 or
more, more preferably 0 or 1 to 3.
Ring A.sup.b is
preferably a "substituted pyridine ring" or a "substituted pyrazole
ring",
more preferably a pyridine ring substituted by substituent(s)
selected from an oxido group, an alkoxy group, a pyrrolidinyl group
substituted by halogen atom(s) and a pyrrolyl group to substituted
by halogen atom(s), or
a pyrazole ring substituted by C.sub.1-6 alkyl group(s) substituted
by substituent(s) selected from a halogen atom, a C.sub.3-7
cycloalkyl group optionally substituted by C.sub.1-6 alkyl group(s)
and a phenyl group.
R.sup.3 is preferably
##STR00025## wherein ring Aa is a 2-pyrroline ring substituted by
substituent(s) selected from a C.sub.1-6 alkyl group optionally
substituted by substituent(s) selected from a halogen atom and a
C.sub.3-7 cycloalkyl group, a C.sub.3-7 cycloalkyl group and an oxo
group, or an imidazole ring optionally substituted by C.sub.1-6
alkyl group(s) wherein the two substituents bonded to the
2-pyrroline ring, in combination, form a C.sub.3-6 cycloalkane; and
ring B.sup.a is a benzene ring substituted by halogen atom(s),
or
##STR00026## wherein ring A.sup.b is a pyridine ring substituted by
substituent(s) selected from an oxido group, an alkoxy group, a
pyrrolidinyl group substituted by halogen atom(s) and a pyrrolyl
group substituted by halogen atom(s), a pyrazole ring substituted
by C.sub.1-6 alkyl group(s) substituted by substituent(s) selected
from a halogen atom, a C.sub.3-7 cycloalkyl group optionally
substituted by C.sub.1-6 alkyl group(s) and a phenyl group, a
thiazole ring, a pyrazine ring, a pyridazine ring, or a pyrimidine
ring.
In another embodiment,
R.sup.3 is preferably
(1) a group represented by
##STR00027## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); R.sup.a and R.sup.b are the same or different and
each is a C.sub.1-6 alkyl group, or R.sup.a and R.sup.b in
combination form a C.sub.3-6 cycloalkane; and R.sup.c is a
C.sub.1-6 alkyl group optionally substituted by substituent(s)
selected from a halogen atom and a C.sub.3-7 cycloalkyl group, or a
C.sub.3-7 cycloalkyl group, (2) a group represented by
##STR00028## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); and R.sup.d and R.sup.e are the same or different
and each is a C.sub.1-6 alkyl group, (3) a pyridyl group
substituted by substituent(s) selected from a C-- alkoxy group, a
pyrrolidinyl group substituted by halogen atom(s) and a pyrrolyl
group substituted by halogen atom(s), (4) a pyrazolyl group
substituted by C.sub.1-6 alkyl group(s) substituted by
substituent(s) selected from a halogen atom, a C.sub.3-7 cycloalkyl
group optionally substituted by C.sub.1-6 alkyl group(s) and a
phenyl group, (5) a thiazolyl group, (6) a pyrazinyl group, (7) a
pyridazinyl group, (8) a pyrimidinyl group, or the like.
R.sup.4 is an optionally substituted C.sub.1-6 alkyl group or an
optionally substituted phenyl group.
Examples of the substituent of the "optionally substituted
C.sub.1-6 alkyl group" for R.sup.4 include substituents selected
from the above-mentioned Substituent Group B. Among them, a halogen
atom and the like are preferable.
The number of the substituents of the "optionally substituted
C.sub.1-6 alkyl group" for R.sup.4 is preferably 0, or 1 or more,
more preferably 0 or 1 to 5.
Examples of the substituent of the "optionally substituted phenyl
group" for R.sup.4 include substituents selected from the
above-mentioned Substituent Group A. Among them, a halogen atom, a
C.sub.1-6 alkyl group optionally substituted by halogen atom(s), a
C.sub.1-6 alkoxy group substituted by substituent(s) selected from
a halogen atom and a phenyl group, and the like are preferable, and
a halogen atom is more preferable.
The number of the substituents of the "optionally substituted
phenyl group" for R.sup.4 is preferably 0, or 1 or more, more
preferably 0 or 1.
R.sup.4 is preferably a C.sub.1-6 alkyl group optionally
substituted by halogen atom(s), a phenyl group optionally
substituted by halogen atom(s), or the like, more preferably a
phenyl group optionally substituted by halogen atom(s), or the
like.
Compound (1) is preferably, for example, the following compound
(1-A), (1-B) and (1-C).
[Compound (1-A)]
A compound which is compound (1) wherein
R.sup.1 is a C.sub.1-6 alkoxy group,
R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl group,
R.sup.3 is
##STR00029## wherein ring Aa is a 2-pyrroline ring substituted by
substituent(s) selected from a C.sub.1-6 alkyl group optionally
substituted by substituent(s) selected from a halogen atom and a
C.sub.3-7 cycloalkyl group, a C.sub.3-7 cycloalkyl group and oxo
group, or an imidazole ring substituted by C.sub.1-6 alkyl group(s)
wherein the two substituents bonded to the 2-pyrroline ring, in
combination, optionally form a C.sub.3-6 cycloalkane; and ring
B.sup.a is a benzene ring substituted by halogen atom(s), or
##STR00030## wherein ring A.sup.b is a pyridine ring substituted by
substituent(s) selected from an oxido group, an alkoxy group, a
pyrrolidinyl group substituted by halogen atom(s) and a pyrrolyl
group substituted by halogen atom(s), a pyrazole ring substituted
by C.sub.1-6 alkyl group(s) substituted by substituent(s) selected
from a halogen atom, a C.sub.3-7 cycloalkyl group optionally
substituted by C.sub.1-6 alkyl group(s) and a phenyl group, a
thiazole ring, a pyrazine ring, a pyridazine ring, or a pyrimidine
ring, and R.sup.4 is a phenyl group optionally substituted by
halogen atom(s), or a salt thereof. [Compound (1-B)]
A compound which is compound (1) wherein
R.sup.1 is a C.sub.1-6 alkoxy group,
R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl group,
R.sup.3 is
(1) a group represented by
##STR00031## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); R.sup.a and R.sup.b are the same or different and
each is a C.sub.1-6 alkyl group, or R.sup.a and R.sup.b in
combination form a C.sub.3-6 cycloalkane; and R.sup.c is a
C.sub.1-6 alkyl group optionally substituted by substituent(s)
selected from a halogen atom and a C.sub.3-7 cycloalkyl group, or a
C.sub.3-7 cycloalkyl group, (2) a group represented by
##STR00032## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); and R.sup.d and R.sup.e are the same or different
and each is a C.sub.1-6 alkyl group, or (3)
##STR00033## wherein ring A.sup.b is a pyridine ring substituted by
substituent(s) selected from an oxido group, an alkoxy group, a
pyrrolidinyl group substituted by halogen atom(s) and a pyrrolyl
group substituted by halogen atom(s), a pyrazole ring substituted
by C.sub.1-6 alkyl group(s) substituted by substituent(s) selected
from a halogen atom, a C.sub.3-7 cycloalkyl group optionally
substituted by C.sub.1-6 alkyl group(s) and a phenyl group, a
thiazole ring, a pyrazine ring, a pyridazine ring, or a pyrimidine
ring, and R.sup.4 is a phenyl group optionally substituted by
halogen atom(s), a salt thereof. [Compound (1-C)]
A compound which is compound (1) wherein R.sup.1 is a C.sub.1-6
alkoxy group, R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl
group, R.sup.3 is (1) a group represented by
##STR00034## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); R.sup.a and R.sup.b are the same or different and
each is a C.sub.1-6 alkyl group, or R.sup.a and R.sup.b in
combination form a C.sub.3-6 cycloalkane; and R.sup.c is a
C.sub.1-6 alkyl group optionally substituted by substituent(s)
selected from a halogen atom and a C.sub.3-7 cycloalkyl group, or a
C.sub.3-7 cycloalkyl group, (2) a group represented by
##STR00035## wherein ring B.sup.a is a benzene ring substituted by
halogen atom(s); and R.sup.d and R.sup.e are the same or different
and each is a C.sub.1-6 alkyl group, (3) a pyridyl group
substituted by substituent(s) selected from a C.sub.1-6 alkoxy
group, a pyrrolidinyl group substituted by halogen atom(s) and a
pyrrolyl group substituted by halogen atom(s), (4) a pyrazolyl
group substituted by C.sub.1-6 alkyl group(s) substituted by
substituent(s) selected from a halogen atom, and a C.sub.3-7
cycloalkyl group optionally substituted by C.sub.1-6 alkyl
group(s), (5) a thiazolyl group, (6) a pyrazinyl group, (7) a
pyridazinyl group, or (8) a pyrimidinyl group, and R.sup.4 is a
phenyl group optionally substituted by halogen atom(s), or a salt
thereof.
As another embodiment, compound (1) is preferably, for example, the
following compound (1-D).
[Compound (1-D)]
A compound which is compound (1) wherein
R.sup.1 is a C.sub.1-6 alkoxy group,
R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl group,
R.sup.3 is
##STR00036## wherein ring A.sup.a is a 2-pyrroline ring substituted
by substituent(s) selected from a C.sub.1-6 alkyl group optionally
substituted by substituent(s) selected from a halogen atom and a
C.sub.3-7 cycloalkyl group, a C.sub.3-7 cycloalkyl group and oxo
group, or an imidazole ring substituted by C.sub.1-6 alkyl group(s)
wherein the two substituents bonded to the 2-pyrroline ring, in
combination, optionally form a C.sub.3-6 cycloalkane; ring B.sup.a
is a benzene ring; and R.sup.5 is a halogen atom, or
##STR00037## wherein ring A.sup.b is a pyridine ring substituted by
substituent(s) selected from an oxido group, an alkoxy group, a
pyrrolidinyl group substituted by halogen atom(s) and a pyrrolyl
group substituted by halogen atom(s), or a pyrazole ring
substituted by C.sub.1-6 alkyl group(s) substituted by
substituent(s) selected from a halogen atom, a C.sub.3-7 cycloalkyl
group optionally substituted by C.sub.1-6 alkyl group(s) and a
phenyl group, and R.sup.4 is a phenyl group optionally substituted
by halogen atom(s), or a salt thereof.
Compound (1) is preferably the compounds of Examples 16 to 21, 23
to 27, 32 to 40 and 42 to 55 or a salt thereof.
In addition, the compounds of Examples 1 to 15, 22, 41 and 55 to
102 which are not contained in compound (1) are also encompassed in
the present invention.
Hereinafter, compound (1) and the compounds of Examples 1 to 15,
22, 41 and 55 to 102 are collectively referred as "the compound of
the present invention".
When the compound of the present invention is a salt, examples of
the salt include metal salts, an ammonium salt, salts with organic
bases, salts with inorganic acids, salts with organic acids, salts
with basic or acidic amino acids, and the like. Preferable examples
of the metal salt include alkali metal salts such as a sodium salt,
a potassium salt and the like; alkaline earth metal salts such as a
calcium salt, a magnesium salt, a barium salt and the like; an
aluminum salt and the like. Preferable examples of the salt with
organic base include salts with trimethylamine, triethylamine,
pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,
triethanolamine, cyclohexylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine and the like. Preferable examples of
the salt with inorganic acid include salts with hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and
the like. Preferable examples of the salt with organic acid include
salts with formic acid, acetic acid, trifluoroacetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid and the like.
Preferable examples of the salt with basic amino acid include salts
with arginine, lysine, ornithine and the like. Preferable examples
of the salt with acidic amino acid include salts with aspartic
acid, glutamic acid and the like. Among them, pharmaceutically
acceptable salts are preferable. For example, when the compound has
an is acidic functional group, examples thereof include inorganic
salts such as alkali metal salts (e.g., a sodium salt, a potassium
salt and the like), alkaline earth metal salts (e.g., a calcium
salt, a magnesium salt, a barium salt and the like) and the like,
an ammonium salt and the like. When the compound has a basic
functional group, examples thereof include salts with inorganic
acids such as hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid and the like, and salts with organic
acids such as acetic acid, phthalic acid, fumaric acid, oxalic
acid, tartaric acid, maleic acid, citric acid, succinic acid,
methanesulfonic acid, p-toluenesulfonic acid and the like.
When the compound of the present invention contains a isomer such
as tautomer, optical isomer, stereoisomer, regioisomer, rotamer and
the like, any isomer and mixture thereof is also encompassed in the
compound of the present invention. In addition, when the compound
of the present invention contains an optical isomer, an optical
isomer resolved from racemate is also encompassed in the compound
of the present invention.
The compound of the present invention may be a crystal, the single
crystal form and mixture thereof are encompassed in the compound of
the present invention.
The compound of the present invention may be a pharmaceutically
acceptable cocrystal or cocrystal salt. Here, the cocrystal or
cocrystal salt means a crystalline substance constituted by two or
more kinds of special solids each having different physical
properties (e.g., structure, melting point, melting heat,
hygroscopicity, solubility, stability and the like) at room
temperature. The cocrystal or cocrystal salt can be produced by a
cocrystallization method known per se.
The compound of the present invention may be a solvate (e.g.,
hydrate and the like), a non-solvate, and both are encompassed in
the compound of the present invention.
The compound labeled or substituted with an isotope (e.g., .sup.2H,
.sup.3H, .sup.11C, .sup.14C, .sup.18F, .sup.35S, .sup.125I and the
like) and the like are also encompassed in the compound of the
present invention. The compound of the present invention labeled or
substituted with an isotope can be used, for example, as a tracer
(PET tracer) used for Positron Emission Tomography (PET), and
therefore is useful in the field of medical diagnosis and the
like.
[Production Method]
The compound of the present invention and the compound as raw
materials can be manufactured by the known means, for example, by
the methods shown in the following schemes and the like.
Hereinafter, "room temperature" indicates a temperature generally
ranging from 0 to 35.degree. C. and "a low temperature" indicates a
temperature generally from -78 to 0.degree. C.
Compound (1) is obtained, for example, according to the method
explained below, an analogous method thereto, or the like.
The symbols used for the compounds in the reaction schemes indicate
the same meanings as mentioned above. In this specification, a
methyl group (--CH.sub.3) is sometimes abbreviated as Me. The
compounds in the schemes can include salts thereof in the cases
when salts can be formed and such salts are similar to the salts of
the compound of the present invention. Further, the compound
obtained in each process can be used directly as a reaction mixture
or as a crude product in the following reactions. However, it can
be isolated from the reaction mixture according to the ordinary
method. The product itself can be easily purified by the known
means of isolation such as extraction, concentration,
neutralization, filtration, distillation, recrystallization,
chromatography and the like. Alternatively, if the compound in the
schemes is commercially available, a commercial product can be used
directly and in addition, those which are manufactured by the known
methods or an analogous method thereof can be used. If the compound
as a raw material contains amino, carboxy, hydroxyl or a
heterocyclic group, the group can be protected by a protective
group that is generally used in the peptide chemistry. In this
case, after reacting, if desirable, target compound can be obtained
by removing the protective group. The protective group can be
introduced or removed by the known methods, for example, based on
the methods described in "Protective Groups in Organic Synthesis,
3.sup.rd Edition" (by Theodora W. Greene, Peter G. M. Wuts,
published in 1999 by Wiley-Interscience Corporation).
Examples of the "X-" include halogen anions (e.g., a chlorine
anion, a bromine anion, an iodine anion etc.), a nitrate ion, and a
phosphate ion.
In these production methods, conversions of each substituents for
R.sup.1-R.sup.4 can be carried out according to a method known per
se, for example, the method described in "Comprehensive Organic
Transformations" (by Richard C. Larock, published in 1999 by
Wiley-VCH).
The following respective processes can be carried out without a
solvent or the compound as a raw material can be dissolved or
suspended in an appropriate solvent prior to the reaction. In this
case, one kind of solvent can be used independently or two or more
solvents can be combined at an appropriate ratio. Specific examples
of the solvents to be used in the production methods for the
compound of the present invention are given as follows:
Alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl
alcohol, 2-methoxyethanol, etc.
Ethers: diethyl ether, diisopropyl ether, diphenyl ether,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.
Aromatic hydrocarbons: benzene, chlorobenzene, toluene, xylene,
etc.
Saturated hydrocarbons: cyclohexane, hexane, etc.
Amides: N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc.
Halogenated hydrocarbons: dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane, etc.
Nitriles: acetonitrile, propionitrile, etc.
Sulfoxides: dimethyl sulfoxide, etc.
Aromatic organic bases: pyridine, lutidine, etc.
Acid anhydrides: acetic anhydride, etc.
Organic acids: formic acid, acetic acid, propionic acid,
trifluoroacetic acid, methanesulfonic acid, etc.
Inorganic acids: hydrochloric acid, sulfuric acid, etc.
Esters: methyl acetate, ethyl acetate, butyl acetate, etc.
Ketones: acetone, methyl ethyl ketone, etc.
Specific examples of bases or deoxidizers that are used in the
production methods for the compound of the present invention are
given as follows:
Inorganic bases: sodium hydroxide, potassium hydroxide, magnesium
hydroxide, etc.
Basic salts: sodium carbonate, potassium carbonate, cesium
carbonate, calcium carbonate, sodium hydrogen carbonate, etc.
Organic bases: triethylamine, diisopropylethylamine, tributylamine,
cyclohexyldimethylamine, pyridine, lutidine,
4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,
N-methylpyrrolidine, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, etc.
Metal alkoxides: sodium methoxide, sodium ethoxide, potassium
tert-butoxide, etc.
Alkali metal hydrides: sodium hydride, potassium hydride, etc.
Metal amides: sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide, etc.
Organolithium reagents: methyl lithium, n-butyl lithium, sec-butyl
lithium, tert-butyl lithium, etc.
Specific examples of acids or acid catalysts that are used in the
production methods for the compound of the present invention are
given as follows:
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,
hydrobromic acid, phosphoric acid, etc.
Organic acids: acetic acid, trifluoroacetic acid, oxalic acid,
phthalic acid, fumaric acid, tartaric acid, maleic acid, citric
acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid,
10-camphorsulfonic acid, etc.
Lewis acids: trifluoroboron ether complex, zinc iodide, anhydrous
aluminum chloride, anhydrous zinc chloride, anhydrous iron
chloride, etc.
When a "heterocyclic compound", "carbamate compound", "acetylene
derivative", "boronic acid derivative" or "organo tin compound" and
the like are bonded to R.sup.3 having a leaving group, the reaction
can be carried out by coupling reaction in the presence of a base,
using both or either of a palladium catalyst and a copper catalyst,
and the like. Examples of the "heterocyclic compound" include
imidazole ring compounds, pyrazole ring compounds, pyrrolidine ring
compounds, piperidine ring compounds, morpholine ring compounds,
oxazepane ring compounds, azetidine ring compounds, pyrrolidone
ring compounds, piperidone ring compounds and the like. Examples of
the "carbamate compound" include oxazolidone ring compounds and the
like. Examples of the "acetylene derivative" include
cyclopropylacetylene and the like. Examples of the "boronic acid
derivative" include (1-methyl-1H-pyrazol-4-yl)boronic acid pinacol
ester and the like. Examples of the "organo tin compound" include
2-(tributylstannyl)-1,3-oxazole and the like.
Examples of the "palladium catalyst" include
tris(dibenzylideneacetone)dipalladium(0),
tetrakistriphenylphosphinepalladium(0) and the like. The "palladium
catalyst" can be used in an amount of about 0.01-1 mol, preferably
0.05-0.2 mol, per 1 mol of the reaction substrate. The "palladium
catalyst" can be used together with a phosphine ligand. When using
a phosphine ligand, it is used in an amount of about 0.01-4 mol,
preferably 0.05-1 mol, per 1 mol of the reaction substrate.
Examples of the "phosphine ligand" include triphenylphosphine,
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the like.
Examples of the "copper catalyst" include copper iodide (CuI),
copper oxide (Cu.sub.2O) and the like. The "copper catalyst" is
used in an amount of about 0.1-1 mol, preferably 0.1-0.5 mol, per 1
mol of the reaction substrate. The "copper catalyst" can be used
together with a ligand such as N,N'-dimethylethane-1,2-diamine,
trans-1,2-diaminocyclohexane, salicylaldoxime and the like. The
ligand is used in an amount of about 0.1-4 mol, preferably 0.1-2
mol, per 1 mol of the reaction substrate. Examples of the "base"
include sodium tert-butoxide and potassium phosphate, and the
amount is about 1 to 10 mol, preferably from 1 to 3 mol, per 1 mol
of the reaction substrate. The reaction is advantageously carried
out without a solvent or in the presence of a solvent inert to the
reaction. While the solvent to be used is not particularly limited
as long as the reaction proceeds, ethers, nitriles and the like are
preferable. The reaction is generally carried out at room
temperature or under heating with reflux, preferably under heating
with reflux. The reaction time is generally from 0.5 to 48 hours,
preferably from 1 to 24 hours.
This coupling reaction can be carried out according to the method
described in "Cross-Coupling Reactions: A Practical Guide (Topics
in Current Chemistry)" (Springer), "Experimental Organometallic
Chemistry for Synthesizing Chemists" (Kodansha) or "Organic
Synthesis using Transition Metals" (Kagaku Dojin), or an analogous
method thereto.
Compound (1) can be synthesized, for example, according to
Production Method A, Production Method B, Production Method C or
the like which is explained below.
Unless otherwise specified, the symbols in each formula in the
reaction schemes are as defined above. In each reaction shown in
the Production Method A-C, "X.sup.-" is a halogen anion (e.g., a
chlorine anion, a bromine anion, an iodine anion etc.), a nitrate
ion or a phosphate ion, and Y is a leaving group such as a halogen
atom (F, Cl, Br, I etc.), a methanesulfonyloxy group, a
trifluoromethanesulfonyloxy group or the like.
[Production Method A]
##STR00038## [Production Method B]
##STR00039## [Production Method C]
##STR00040##
Step 1 is a method of producing compound (3) by reacting compound
(2) with a diazotizing agent. When desired, the reaction can be
carried out in the presence of an acid.
Examples of the diazotizing agent include alkali metal nitrites
such as sodium nitrite, potassium nitrite and the like; alkyl
nitrites having 2 to 6 carbon atoms such as t-butyl nitrite,
isoamyl nitrite and the like; nitrosyl chloride, nitrosylsulfuric
acid, nitric oxide and the like. Among them, sodium nitrite is
preferable from the aspects of low cost and easy availability. In
addition, an alkyl nitrite is preferable from the aspects of high
reactivity. Since an alkali metal nitrite is solid at ambient
temperature, it may be dissolved in water prior to use.
Examples of the "acid" include hydrochloric acid, sulfuric acid,
acetic acid and the like, and the acid may be used in a mixture of
two or more thereof.
The amount of the diazotizing agent to be used is 1-5 mol,
preferably 1-2 mol, per 1 mol of compound (2), from the aspects of
high reactivity and economic efficiency. This reaction is generally
carried out at room temperature or low temperature, preferably at
-30.degree. C. to 0.degree. C.
The reaction time is generally 1 min-3 hr, preferably 1 min-1
hr.
The reaction is advantageously carried out without a solvent or in
the presence of a solvent inert to the reaction. While the solvent
to be used is not particularly limited as long as the reaction
proceeds, water is preferable.
Step 2 is a method of producing compound (5) or compound (16) by
reacting compound (3) in the presence of compound (4) or compound
(15).
This step can be carried out according to the method described in
Tetrahedron Lett., 2008, 49(14), 2262-2264, or an analogous method
thereto. When desired, the reaction can be carried out in the
presence of a base.
The amount of compound (4) or compound (15) to be used is about 1-5
mol, preferably 1-2 mol, per 1 mol of compound (3).
Examples of the "base" include sodium acetate.
The amount of the "base" to be used is generally 1-10 equivalents,
preferably 2-6 equivalents, relative to compound (3).
The reaction is advantageously carried out without a solvent or in
the presence of a solvent inert to the reaction. While the solvent
to be used is not particularly limited as long as the reaction
proceeds, a mixed solvent of an alcohol and water is
preferable.
This reaction is generally carried out at room temperature, or at
low temperature under cooling in ice bath.
The reaction time is generally 5 sec-24 hr, preferably 5 sec-1
hr.
Step 3 is a method of producing compound (6), compound (10) or
compound (1) from compound (5), compound (9) or compound (16). The
reaction can be carried out in the presence of
N,N-dimethylformamide dimethyl acetal, N,N-dimethylacetamide
dimethyl acetal and the like as a solvent.
This step can be carried out according to the method described in
Journal of Heterocyclic Chemistry, 1981, 18, 333-334, or an
analogous method thereto.
This reaction is generally carried out under heating with reflux,
preferably at 100.degree. C.-150.degree. C.
The reaction time is generally 1-10 hr, preferably 1-hr.
Step 4 is a method of producing compound (7) from compound (6). The
reaction can be carried out under an acidic or basic condition.
This reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, an
alcohol, a solvent mixed with water, and an ether are
preferable.
Examples of the "acid" include inorganic acids.
Examples of the "base" include inorganic bases such as sodium
hydroxide, potassium hydroxide and the like. In addition, lithium
hydroxide can also be used.
The amount of the acid or base to be used is about 1-10 mol,
preferably 1-5 mol, per 1 mol of compound (6).
The reaction is generally carried out at room temperature or under
heating, preferably at room temperature.
The reaction time is generally 1-48 hr, preferably 3-hr.
Step 5 is a method of producing compound (8) from compound (7).
Compound (8) can be produced using N,O-dimethylhydroxylamine
hydrochloride and a condensing agent, in the presence of a base
such as triethylamine, N,N-diisopropylethylamine and the like.
Alternatively, Compound (8) can also be produced by converting the
substrate carboxylic acid into the corresponding acid halide, and
then reacting the acid halide with N,O-dimethylhydroxylamine
hydrochloride.
Examples of the "condensing agent" include
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride in the
presence of 1-hydroxybenzotriazole.
The reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, a
nitrile, an ether and an amide are preferable.
The amount of the N,O-dimethylhydroxylamine hydrochloride to be
used is about 1-5 mol, preferably 1-3 mol, per 1 mol of compound
(7).
The amount of the condensing agent to be used is about 1-5 mol,
preferably 1-3 mol, per 1 mol of compound (7).
The amount of the base (e.g., triethylamine,
N,N-diisopropylethylamine and the like) to be used is about 1-10
mol, preferably 2-3 mol, per 1 mol of compound (7).
The reaction is generally carried out at room temperature or under
heating, preferably at room temperature.
The reaction time is generally 1-48 hr, preferably 5-hr.
Compound (8) can be synthesized by reacting the acid halide with
N,O-dimethylhydroxylamine hydrochloride in the presence of a base
such as triethylamine and the like.
The reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, an
ether, an ester and an amide are preferable.
The amount of the N,O-dimethylhydroxylamine hydrochloride to be
used is about 1-5 mol, preferably 1-3 mol, per 1 mol of compound
(7).
The amount of the base (e.g., triethylamine and the like) to be
used is about 1-10 mol, preferably 2-3 mol, per 1 mol of compound
(7).
This reaction is generally carried out under ice-cooling or at room
temperature, preferably under ice-cooling.
The reaction time is generally 0.5-5 hr, preferably 1-3 hr.
Alternatively, compound (8) can be produced by reacting compound
(6) with trimethylaluminum and N,O-dimethylhydroxylamine
hydrochloride in the presence of an organic base. The amount of the
organic base, trimethylaluminum and N,O-dimethylhydroxylamine
hydrochloride to be used is about 1-10 mol, preferably 2-5 mol, per
1 mol of compound (6). This reaction is advantageously carried out
without a solvent or with a solvent inert to the reaction. While
the solvent to be used is not particularly limited as long as the
reaction proceeds, a halogenated hydrocarbon is preferable. This
reaction is generally carried out under ice-cooling or at room
temperature, preferably under ice-cooling. The reaction time is
generally 1-24 hr, preferably 1-5 hr.
Step 6 is a method of producing compound (9) from compound (8).
Compound (9) can be produced using an "alkylating agent" such as
the Grignard reagent, an organolithium reagent and the like.
The reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, an
ether is preferable.
The amount of the "alkylating agent" to be used is about 1-10 mol,
preferably 2-3 mol, per 1 mol of compound (8).
This reaction is generally carried out at -78.degree. C. or under
ice-cooling, preferably at -78.degree. C. The reaction time is
generally 1-10 hr, preferably 1-3 hr.
Step 7 is a method of producing compound (1) by reacting compound
(10) in the presence of compound (11).
The amount of compound (11) to be used is about 1-10 mol,
preferably about 2-5 mol, per 1 mol of compound (10).
The reaction is advantageously carried out without a solvent or in
the presence of a solvent inert to the reaction. While the solvent
to be used is not particularly limited as long as the reaction
proceeds, an alcohol, an organic acid and a mixed solvent thereof
are preferable.
This reaction is generally carried out under ice-cooling, at room
temperature or under heating with reflux, preferably at 0.degree.
C.-150.degree. C.
The reaction time is generally 0.1-10 hr, preferably 0.5-5 hr.
This step is can be carried out according to the method described
in Journal of Heterocyclic Chemistry, 1981, 18, 333-334, or an
analogous method thereto.
In this step, R.sup.4 is an optionally substituted C.sub.1-6 alkyl
group or an optionally substituted phenyl group.
Step 8 is a method of producing compound (14) from compound (12).
Compound (14) can be produced by reacting compound (12) with
compound (13) in the presence of an organolithium reagent such as
n-butyllithium and the like.
The organolithium reagent is used in an amount of about 1-10 mol,
preferably 1-3 mol, per 1 mol of compound (12), and compound (13)
is used in an amount of about 1-10 mol, preferably 1-3 mol, per 1
mol of compound (12).
The reaction is advantageously carried out without a solvent or in
the presence of a solvent inert to the reaction. While the solvent
to be used is not particularly limited as long as the reaction
proceeds, an ether, particularly tetrahydrofuran is preferable.
This reaction is generally carried out at room temperature or low
temperature, preferably at -78.degree. C.-0.degree. C.
The reaction time is generally 0.5 hr-12 hr, preferably 1 hr-5
hr.
Step 9 is a method of producing compound (15) from compound (14).
Compound (15) can be produced using an appropriate oxidation
reaction.
Examples of the "oxidation reaction" include Swern oxidation
reaction, oxidation reaction using an oxidant such as sulfur
trioxide pyridine complex, pyridinium chlorochromate and the like.
In the case of the oxidation reaction using an oxidant, the oxidant
is used in an amount of about 1-10 mol, preferably 1-3 mol, per 1
mol of compound (14). The reaction is advantageously carried out
without a solvent or with a solvent inert to the reaction. While
the solvent to be used is not particularly limited as long as the
reaction proceeds, dimethyl sulfoxide, a halogenated hydrocarbon
and an ester are preferable. This reaction is preferably carried
out at low temperature or room temperature. The reaction time is
generally 1-10 hr, preferably 1-3 hr.
This step can be carried out according to the method described in
Comprehensive Organic Transformations (WILEY-VCH), or Oxidation in
Organic Chemistry (American Chemical Society), or an analogous
method thereto.
Step 10 is a method of producing compound (18) from compound (17).
Compound (18) can be produced by reacting compound (17) with benzyl
bromide and the like in the presence of an alkali metal hydride
such as sodium hydride and the like.
The alkali metal hydride is used in an amount of about 1-10 mol,
preferably 1-3 mol, per 1 mol of compound (17), and the benzyl
bromide is used in an amount of about 1-10 mol, preferably 1-3 mol,
per 1 mol of compound (17).
In addition, an additive such as tetrabutylammonium iodide and the
like may be added to the reaction system to promote the reaction.
The amount of the additive (e.g., tetrabutylammonium iodide and the
like) to be used is about 0.1-3 equivalents, preferably 0.1-1
equivalents, relative to compound (17).
This reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, an
amide, an ether and a mixed solvent thereof are preferable.
This reaction is generally carried out at room temperature or low
temperature, preferably at 0.degree. C.--room temperature.
The reaction time is generally 0.5 hr-48 hr, preferably 1 hr-24
hr.
Step 11 is a method of producing compound (20) from compound (18)
and compound (19). Compound (20) can be produced using a palladium
catalyst in the presence of a base.
The amount of compound (19) to be used is about 1-10 mol,
preferably about 1-3 mol, per 1 mol of compound (18).
Examples of the "base" include potassium acetate, potassium
carbonate and the like. The amount thereof is about 1-10 mol,
preferably 1-3 mol, per 1 mol of compound (18).
Examples of the "palladium catalyst" include
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II),
tetrakis(triphenylphosphine)palladium(0) and the like. The amount
thereof is about 0.01-0.5 mol, preferably 0.03-0.1 mol, per 1 mol
of compound (18).
The reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, a
mixed solvent of an alcohol and water, an aromatic hydrocarbon, an
ether, an amide and the like are preferable.
This reaction is generally carried out at room temperature or under
heating with reflux, preferably under heating with reflux.
The reaction time is generally 1-48 hr, preferably 10-20 hr.
This step can be carried out according to the method described in
Org. Lett., 2006, 8, 1787-1789, or an analogous method thereto.
Step 12 is a method of producing compound (21) from compound (20).
Compound (21) can be produced by hydrogenation reaction in the
presence of a catalyst such as palladium on carbon and the
like.
This reaction can be carried out according to a method known per
se, for example, the method described in Wiley-Interscience, 1999,
"Protective Groups in Organic Synthesis, 3.sup.rd Ed." (Theodora W.
Greene, Peter G. M. Wuts), or the like.
Step 13 is a method of producing compound (1) from compound (21).
Compound (1) can be produced by reacting compound (21) with
compound (22) in the presence of a base.
The amount of compound (22) to be used is about 1-10 mol,
preferably 1-3 mol, per 1 mol of compound (21). The base to be used
is preferably a basic salt such as cesium carbonate and the like.
The base is used in an amount of about 1-10 mol, preferably 1-3
mol, per 1 mol of compound (21).
The reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, an
amide, a sulfoxide and the like are preferable.
This reaction is generally carried out at room temperature or under
heating with reflux, preferably at 100.degree. C.-150.degree. C.
under heating with reflux.
The reaction time is generally 1-120 hr, preferably 10-72 hr.
This reaction may be carried out in the presence of a copper
catalyst, while it is not particularly limited as long as the
reaction proceeds. Examples of the copper catalyst include copper
iodide (CuI) and the like. The copper catalyst is used in an amount
of about 0.1-1 mol, preferably 0.1-0.5 mol, per 1 mol of compound
(21). In addition, a ligand such as
4,7-dimethoxy-1,10-phenanthroline and the like may be used. The
ligand is used in an amount of about 0.1-1 mol, preferably 0.1-0.5
mol, per 1 mol of compound (21).
The reaction is advantageously carried out without a solvent or
with a solvent inert to the reaction. While the solvent to be used
is not particularly limited as long as the reaction proceeds, an
amide, a sulfoxide and the like are preferable.
This reaction is generally carried out at room temperature or under
heating with reflux, preferably at 100.degree. C.-150.degree. C.
under heating with reflux.
The reaction time is generally 1-120 hr, preferably 10-72 hr.
The compounds of Examples 1 to 15, 22, 41 and 55 to 102 can be
produced according to each Example mentioned below.
The compound of the present invention obtained by the
aforementioned methods can be isolated or purified by the ordinary
separation means such as recrystallization, distillation,
chromatography and the like. When the compound of the present
invention thus obtained is obtained in a free form, they can be
converted to their salts by the known methods or an analogous
method thereof (e.g., neutralization, etc.), or in reverse, if they
are obtained in the salt, they can be converted to a free form or
other salts by the known methods or an analogous method
thereof.
When the compound of the present invention is present as a
configuration isomer, a diastereomer, a conformer and the like,
they can be respectively isolated when desired by the
above-mentioned separation and purification means. When the
compound of the present invention is a racemate, it can be
separated into a d-form and an l-form by the ordinary optical
separation means.
The starting compound used for the production of the compound of
the present invention may be a salt as long as the reaction is not
impaired. Examples of such salt include salts similar to those of
the compound of the present invention.
In any of the above mentioned production methods or processes, if
desired, the compound of the present invention can be synthesized
by further applying one or combination of known reactions such as
protection-deprotection reactions, acylation reactions, alkylation
reactions, hydrogenation reactions, oxidation reactions, reduction
reactions, carbon chain extension reactions, substituent exchanging
reactions and the like.
The compound of the present invention may be used as a prodrug. A
prodrug of the compound of the present invention means a compound
which is converted to the compound of the present invention by a
reaction using enzyme, gastric acid, etc. under the physiological
conditions in the living body, that is, a compound which is
converted to the compound of the present invention by enzymatical
oxidation, reduction, hydrolysis, etc.; a compound which is
converted to the compound of the present invention by hydrolysis
etc. using gastric acid, etc.
A prodrug of the compound of the present invention may be a
compound obtained by subjecting an amino group in the compound of
the present invention to an acylation, alkylation or
phosphorylation (e.g., a compound obtained by subjecting an amino
group in the compound of the present invention to an
eicosanoylation, alanylation, pentylaminocarbonylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation, tert-butylation, etc.); a compound obtained
by subjecting a hydroxy group in the compound of the present
invention to an acylation, alkylation, phosphorylation or boration
(e.g., a compound obtained by subjecting an hydroxy group in the
compound of the present invention to an acetylation,
palmitoylation, propanoylation, pivaloylation, succinylation,
fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.);
a compound obtained by subjecting a carboxyl group in compound of
the present invention to an esterification or amidation (e.g., a
compound obtained by subjecting a carboxyl group in the compound of
the present invention to an ethyl esterification, phenyl
esterification, carboxymethyl esterification, dimethylaminomethyl
esterification, pivaloyloxymethyl esterification,
ethoxycarbonyloxyethyl esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,
cyclohexyloxycarbonylethyl esterification, methylamidation, etc.)
and the like. Any of these compounds can be produced from the
compound of the present invention by a method known per se. A
prodrug for the compound of the present invention may also be one
which is converted into the compound of the present invention under
a physiological condition, such as those described in IYAKUHIN no
KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of
Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).
The compound of the present invention has an excellent PDE10A
inhibitory activity, and for example, is useful as a medicament for
preventing or treating the following diseases and symptoms.
psychotic disorder (e.g., brief psychotic disorder, induced
delusional disorder);
psychotic diseases induced by alcohol, amphetamine, cannabinoid,
cocaine, hallucinogenic drug, obesity, opioids, phencyclidine and
the like;
delusional disorder;
anxiety disorder;
movement disorder;
mood disorder;
major depression;
depression overlapping with psychotic disorders including
delusional disorder or schizophrenia;
major depressive episode of mild, moderate or severe type;
manic or mixed episode;
hypomanic episode;
depressive episode with atypical features;
depressive episode with melancholic features;
depressive episode with catatonic features;
mood episode with postpartum onset;
post-stroke depression;
dysthymic disorder;
minor depression;
autism;
drug addiction;
neurodegenerative disease;
neurodegeneration associated with brain trauma;
neurodegeneration associated with cerebral stroke;
neurodegeneration associated with cerebral infarction;
hypoglycemia-induced neurodegeneration;
neurodegeneration associated with epilepsy seizure;
neurodegeneration associated with neurotoxin;
multiple system atrophy;
Alzheimer's disease;
dementia;
multi-infarct dementia;
alcoholic dementia or other drug-related dementia;
dementia associated with intracranial tumor or cerebrum trauma;
dementia associated with Huntington's disease or Parkinson's
disease;
AIDS-related dementia syndrome;
frontotemperal dementia;
delirium;
amnestic disorder;
post-traumatic stress disorder;
mental retardation (hypophrenia);
learning disorder (e.g., dyslexia, dyscalculia, agraphia);
attention-deficit hyperactivity disorder;
age-related cognitive decline;
premenstrual dysphoric disorder;
bipolar disorder including bipolar I disorder or bipolar II
disorder;
cyclothymic disorder;
Parkinson's disease;
Huntington's disease;
delusion;
schizophrenia (e.g., paranoid schizophrenia, disorganized
schizophrenia, catatonic schizophrenia, undifferentiated
schizophrenia, residual schizophrenia);
schizoaffective disorder;
schizoaffective disorder of the delusional type or the depressive
type;
personality disorder of the paranoid type;
personality disorder of the schizoid type;
obesity;
metabolic syndrome;
non-insulin dependent diabetes;
glucose intolerance.
In particular, the compound of the present invention is useful for
preventing or treating schizophrenia.
The compound of the present invention is superior in metabolic
stability, so that the compound of this invention can be expected
to have an excellent therapeutic effect on the above-mentioned
diseases even in a low dose.
In particular, since compound (1) has a group represented by
R.sup.1 (optionally substituted alkoxy group), it shows high PDE10A
inhibitory activity and high PDE10A selectivity, and can prevent
oxidation reactions such as epoxidation and the like.
A preferable embodiment of the present invention, which is a
compound of the present invention wherein R.sup.1 is a methoxy
group, R.sup.3 is a substituted pyridinyl group, a substituted
pyrazolyl group, a substituted oxoindolyl group or a substituted
benzimidazolyl group, and R.sup.4 is a phenyl group, shows high
solubility and good in vivo kinetics.
Particularly, when R.sup.3 is a fused ring of the formula
##STR00041## which is formed by ring B.sup.a and ring A.sup.a, the
activity increases on space model by specifying the substitutable
position of the fused ring for R.sup.5. Furthermore, it is
considered that the presence of substituent for R.sup.5 suppresses
the toxicity and improves the selectivity of PDE10A inhibitory
activity.
In addition, when R.sup.3 is a substituted pyridyl group, a salt
can be formed, and the solubility can be improved. Furthermore,
when R.sup.3 is an optionally substituted pyrazolyl group,
improvement of solubility and improvement of Blood-Brain Barrier
Penetration can be expected, since the molecular weight
decreases.
Since the compound of the present invention has low toxicity (e.g.,
more superior as medicament in terms of acute toxicity, chronic
toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity,
drug interaction, carcinogenicity and the like), it can be safely
administered as it is as a medicament, or as a pharmaceutical
composition obtained by mixing with a pharmaceutically acceptable
carrier etc., orally or parenterally to a mammal (e.g., human,
monkey, bovine, horse, swine, mouse, rat, hamster, rabbit, cat,
dog, sheep, goat etc.).
The compound of the present invention can be used singly as a
medicament according to a method known per se (e.g., the method
described in the Japanese Pharmacopoeia etc.) as a production
method of a pharmaceutical preparation. In addition, the compound
of the present invention can be used as a pharmaceutical
composition by mixing with a pharmacologically acceptable
carrier.
A medicament containing the compound of the present invention can
be safely administered as, for example, tablets (inclusive of
sugar-coated tablet, film-coated tablet, sublingual tablet, orally
disintegrable tablet, buccal, etc.), pills, powders, granules,
capsules (inclusive of soft capsule, and microcapsule), troches,
syrups, liquids, emulsions, suspensions, controlled-release
preparations (e.g., quick-release preparation, sustained-release
preparation, sustained-release microcapsule), aerosols, films
(e.g., orally disintegrable film, oral mucosal adhesive film),
injections (e.g., subcutaneous injection, intravenous injection,
intramuscular injection, intraperitoneal injection), drip infusion,
percutaneous absorbent, ointment, lotion, patch, suppositories
(e.g., rectal suppository, vaginal suppository), pellets,
transnasal preparations, pulmonary preparations (inhalant), eye
drops and the like, in an oral or parenteral route (e.g.,
intravenous, intramuscular, subcutaneous, intraorgan, intranasal,
intradermal, ophthalmic instillation, intracerebral, intrarectal,
intravaginal, intraperitoneal, and directly to lesion).
As a pharmaceutical acceptable carrier, common organic or inorganic
carrier substances are used as formulation raw materials. Carriers
are added as vehicles, lubricants, binders and disintegrants in the
solid formulations; and as solvents, solubilizing agents,
suspending agents, isotonization agents, buffers, soothing agents
etc. in the liquid formulations. If desired, formulation additives
such as antiseptics, antioxidants, colorants, sweeteners, etc. can
be used.
Favorable examples of the vehicles are as follows: lactose,
sucrose, D-mannitol, D-sorbitol, starch, .alpha.-starch, dextrin,
microcrystalline cellulose, low-substituted hydroxypropyl
cellulose, sodium carboxymethylcellulose, gum Arabic, pullulan,
light anhydrous silicic acid, synthetic aluminum silicate and
magnesium metasilicic aluminate.
Favorable examples of the lubricants include magnesium stearate,
calcium stearate, talc and colloidal silica.
Favorable examples of the binders are as follows: .alpha.-starch,
sucrose, gelatin, gum Arabic, methylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose,
microcrystalline cellulose, sucrose, D-mannitol, trehalose,
dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose and polyvinyl pyrrolidone.
Favorable examples of the disintegrants are as follows: lactose,
sucrose, starch, carboxymethylcellulose, calcium
carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl
starch, light anhydrous silicic acid and low-substituted
hydroxypropylcellulose.
Favorable examples of the solvents are as follows: water for
injection, physiological saline, Linger solution, alcohol,
propylene glycol, polyethylene glycol, sesame oil, corn oil, olive
oil and cottonseed oil.
Favorable examples of the solubilizing agents are as follows:
polyethylene glycol, propylene glycol, D-mannitol, trehalose,
benzyl benzoate, ethanol, tris-aminomethane, cholesterol,
triethanolamine, sodium carbonate, sodium citrate, sodium
salicylate and sodium acetate.
Favorable examples of the suspending agents are as follows:
surfactants such as stearyl triethanolamine, sodium lauryl sulfate,
laurylamino propionic acid, lecithin, benzalkonium chloride,
benzethonium chloride, and glycerin monostearate; hydrophilic
polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium
carboxymethylcellulose, methylcellulose, hydroxymethyl cellulose,
hydroxyethyl cellulose and hydroxypropyl cellulose, etc.;
polysorbates, and polyoxyethylene hydrogenated castor oil.
Favorable examples of the isotonization agents include sodium
chloride, glycerin, D-mannitol, D-sorbitol and glucose.
Favorable examples of the buffers include buffer solutions of
phosphates, acetates, carbonates and citrates, etc.
Favorable examples of the soothing agents include benzyl
alcohol.
Favorable examples of antiseptics include para-oxybenzoic acid
esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
dehydroacetic acid and sorbic acid.
Favorable examples of antioxidants include sulfites and
ascorbates.
Favorable examples of the colorants include water soluble edible
tar dyes (e.g., edible dyes such as Food Red No. 2 and No. 3, Food
Yellow No. 4 and No. 5, Food Blue No. 1 and 2, etc.); water
insoluble lake dyes (e.g., aluminum salts of the aforementioned
water soluble edible tar dyes), natural dyes (e.g.,
.beta.-carotene, chlorophyll, ferric oxide red).
Favorable examples of the sweeteners include sodium saccharin,
dipotassium glycyrrhizinate, aspartame and stevia.
The pharmaceutical compositions of the present invention can be
manufactured by the common methods in the field of formulation
technology, for example, methods listed in the Japanese
pharmacopoeia, etc. Specific production methods for formulations
are described in detail below.
The content of the compound of the present invention in the
pharmaceutical compositions of the present invention varies based
on the dosage forms, dosages of the compound of the present
invention, etc. For example, the content approximately ranges from
about 0.01 to 100 wt % and preferably from 0.1 to 95 wt % relative
to the entire amount of the composition.
The dosage of the compound of the present invention depends upon
administration subjects, administration routes, target diseases,
symptoms, etc. For example, in the case of oral administration in
patients with schizophrenia (adults, bodyweight of about 60 kg),
generally a single dose ranges from about 0.1 to about 20 mg/kg
bodyweight, preferably from about 0.2 to about 10 mg/kg bodyweight,
further preferably from about 0.5 to about 10 mg/kg bodyweight, and
this dosage is preferably administered once daily or several times
daily (e.g., 3 times).
The compound of the present invention may be used in combination
with other active ingredients. Examples of the drug that can be
used in combination or concomitantly with the compound of the
present invention (hereinafter sometimes to be abbreviated as
concomitant drug) include the following.
A therapeutic drug for psychotic diseases, particularly
schizophrenia, or bipolar disorder, obsessive disorder, major
depression, Parkinson's disease, Huntington's disease, Alzheimer's
disease, cognitive dysfunction and memory disorders [atypical
antipsychotic agents (e.g., clozapine, olanzapine, risperidone,
aripiprazole, blonanserin, iloperidone, asenapine, ziprasidone,
quetiapine, zotepine etc.), typical antipsychotic agents (e.g.,
haloperidol, chlorpromazine etc.), selective serotonin reuptake
inhibitor (e.g., paroxetine, sertraline, fluvoxamine, fluoxetine
etc.), selective serotonin.noradrenaline reuptake inhibitor (e.g.,
milnacipran, venlafaxine etc.), selective noradrenaline-dopamine
reuptake inhibitor (e.g., bupropion etc.), tetracyclic
antidepressant (e.g., amoxapine, clomipramine etc.), tricyclic
antidepressant (e.g., imipramine, amitriptyline etc.), other
antidepressant (e.g., NS-2359, Lu AA21004, DOV21947 etc.),
.alpha..sub.7 nicotine receptor agonist, .alpha..sub.7 nicotine
receptor activity modulator, .alpha..sub.7 nicotine receptor
partial modulator (e.g., SSR-180711, PNU-120596 etc.), PDE1
inhibitor, PDE2 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDE7
inhibitor, PDE9 inhibitor, other PDE inhibitor, calcium channel
inhibitor, NK2 antagonist, NK3 antagonist, muscarine type M1
acetylcholine receptor activity modulator, muscarine type M2
acetylcholine receptor activity modulator, adenosine receptor
modulator, muscarine type M4 acetylcholine receptor activity
modulator, muscarine type M5 acetylcholine receptor activity
modulator, adenosine receptor modulator, glycine transporter 1
inhibitor (e.g., ALX5407, SSR504734 etc.), glutamate enhancer
(e.g., ampakine), NMDA-type glutamate receptor modulator, metabolic
glutamate receptor modulator (e.g., CDPPB, MPEP etc.), antianxiety
drug (benzodiazepine (e.g., diazepam, etizolam etc.), serotonin
5-HT.sub.1A agonist (e.g., tandospirone etc.)), hypnotic pills
(benzodiazepine (e.g., estazolam, triazolam etc.),
non-benzodiazepine (e.g., zolpidem etc.), melatonin receptor
agonist (e.g., ramelteon etc.)), .beta. amyloid vaccine, .beta.
amyloid degrading enzyme etc., brain function activator (e.g.,
aniracetam, nicergoline etc.), cannabinoid modulator,
cholinesterase inhibitor (e.g., donepezil, rivastigmine,
galanthamine), therapeutic drug for Parkinson's disease (e.g.,
dopamine receptor agonist (L-DOPA, bromocriptine, pergolide,
talipexole, pramipexole, cabergoline, amantadine etc.), monoamine
oxidase inhibitor (deprenyl, selegiline, remacemide, riluzole
etc.), anticholinergic agent (e.g., trihexyphenidyl, biperiden
etc.), COMT inhibitor (e.g., entacapone etc.), a therapeutic drug
for amyotrophic lateral sclerosis (e.g., riluzole etc.,
neurotrophic factor etc.), apoptosis inhibitor (e.g., CPI-1189,
IDN-6556, CEP-1347 etc.), neuronal differentiation-regeneration
promoter (e.g., leteprinim, xaliproden (SR-57746-A), SB-216763
etc.)], and a therapeutic drug for diseases easily associated with
schizophrenia [therapeutic drug for diabetes (PPAR acting drug
(e.g., agonist, inhibitor, pioglitazone, rosiglitazone,
troglitazone), insulin secretagogue (e.g., sulfonylurea drugs,
non-sulfonylurea drugs), a glucosidase inhibitor (e.g., acarbose),
insulin sensitizer (e.g., PPAR-.gamma. acting drug, PTP-1B
inhibitor, DPP-4 inhibitor, 11.beta.-HSD inhibitor), liver
gluconeogenesis inhibitor (e.g., glucagon antagonist, metformin),
insulin, insulin derivative), antiobesity drug (.beta.-3 agonist,
CB1 agonist, neuropeptide Y5 inhibitor, anorexigenic agent (e.g.,
sibutramine), lipase inhibitor (e.g., orlistat)), a therapeutic
drug for hyperlipidemia such as a cholesterol lowering agent and
the like (statin (e.g., pravastatin sodium, atrovastatin,
simvastatin, rosuvastatin etc.), fibrate (e.g., clofibrate etc.),
squalene synthase inhibitor), antihypertensive agent, non-steroidal
anti-inflammatory agent (e.g., meloxicam, teoxicam, indomethacin,
ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin etc.),
disease-modified anti-rheumatic drug (DMARDs), anticytokine agent
(TNF inhibitor, MAP kinase inhibitor and the like), steroid drug
(e.g., dexamethasone, hexestrol, cortisone acetate etc.), sex
hormone or a derivative thereof (e.g., progesterone, estradiol,
estradiol benzoate etc.), parathyroid hormone (PTH), calcium
receptor antagonist etc.]
The dosage form of concomitant drugs with the compound of the
present invention is not particularly limited and is acceptable as
long as the compound of the present invention is combined with
concomitant drugs at the time of administration. Examples of such
dosage forms are as follows
(1) Administration of a single formula obtained simultaneous
formulation of the compound of the present invention with a
concomitant drug,
(2) Simultaneous administration via the same administration route
for two kinds of formulas obtained by independent formulations of
the compound of the present invention and a concomitant drug,
(3) Administrations at different times via the same administration
route for two kinds of formulas obtained by independent
formulations of the compound of the present invention and a
concomitant drug,
(4) Simultaneous administration via different administration routes
for two kinds of formulas obtained by independent formulations of
the compound of the present invention and a concomitant drug,
(5) Administrations at different times via different administration
routes for two kinds of formulas obtained by independent
formulations of the compound of the present invention and a
concomitant drug (e.g., administration in the order of the compound
of the present invention and then a concomitant drug, or
administration in the reversed order). These dosage forms are
summarized below and abbreviated as a combination drug of the
present invention.
When administering the combination drug of the present invention, a
concomitant drug and the compound of the present invention can be
administered at the same time, but the compound of the present
invention can be administered after a concomitant drug is
administered or after the compound of the present invention is
administered, a concomitant drug can be administered. When
administering at different times, the time difference depends upon
the active ingredients to be administered, dosage forms and methods
of administration. For example, when a concomitant drug is
administered first, the compound of the present invention can be
administered within 1 min to 3 days, preferably within 10 min to 1
day and more preferably within 15 min to 1 hour after the
concomitant drug is administered. However, if the compound of the
present invention is administered first, a concomitant drug can be
administered within 1 min to 1 day, preferably within 10 min to 6
hours and more preferably within 15 min to 1 hour after the
compound of the present invention is administered.
If there are no problems with side effects of the concomitant
drugs, any dosages can be set. A daily dosage as a concomitant drug
depends upon administration subjects, administration routes, target
diseases, symptoms, etc. For example, in the case of oral
administration in patients with schizophrenia (adults, bodyweight
of about 60 kg), a normal once dosage ranges from about 0.1 to
about 20 mg/kg bodyweight, preferably from about 0.2 to about 10
mg/kg bodyweight and more preferably from about 0.5 to about 10
mg/kg bodyweight. It is preferable that this dosage is administered
once daily to several times daily (e.g., 3 times).
If the compound of the present invention is used in combination
with a concomitant drug, the respective dosages can be reduced
within a safe range with consideration of the opposite effects of
the respective drugs.
The combination drug of the present invention exhibits low
toxicity. For example, the compound of the present invention or
(and) the aforementioned concomitant drug can be combined with a
pharmaceutically acceptable carrier according to the known method
to prepare a pharmaceutical composition such as tablets (including
sugar-coated tablet and film-coated tablet), powders, granules,
capsules (including soft capsule), liquids, injections,
suppositories, sustained-release preparation, etc. These
compositions can be administered safely orally or parenterally.
The pharmaceutically acceptable carriers that may be used for
manufacturing the combination drug of the present invention can be
the same as those used in the pharmaceutical composition of the
present invention as mentioned above.
A combination ratio between the compound of the present invention
and a concomitant drug in the combination drug of the present
invention can be selected appropriately based on the administration
subjects, administration routes and diseases, etc.
The aforementioned concomitant drugs can be used in combination at
an appropriate proportion if two or more drugs are combined.
A dosage of the concomitant drug can be selected appropriately
based on the dosages used clinically. In addition, a mixing ratio
between the compound of the present invention and a concomitant
drug can be selected appropriately based on the administration
subjects, administration routes, target diseases, symptoms,
combinations, etc. For example, if the administration subject is
humans, a concomitant drug may be used in an amount ranging from
0.01 to 100 parts by weight relative to 1 part by weight of the
compound of the present invention.
For example, the content of the compound of the present invention
in the combination drug of the present invention varies with the
form of formulations. Generally, it is present in a range from
about 0.01 to 99.9 wt %, preferably from about 0.1 to about 50 wt %
and more preferably from about 0.5 to about 20 wt % relative to the
entire formula.
The content of a concomitant drug in the combination drug of the
present invention varies with the drug form of formulations.
Generally it is present in a range from about 0.01 to 99.9 wt %,
preferably from about 0.1 to about 50 wt % and more preferably from
about 0.5 to about 20 wt % relative to the entire formula.
The content of an additive such as carriers in the combination drug
of the present invention varies with the drug form of formulations.
Generally it is present in a range from about 1 to 99.99 wt % and
preferably from about 10 to about 90 wt % relative to the entire
formula.
When the compound of the present invention and a concomitant drug
are formulated independently, the same contents can be applied.
Since the dosages may fluctuate under various conditions as
mentioned above, a dosage less than the dosages may be sufficient
or it may be necessary to administer at a dosage exceeding the
range.
EXAMPLES
The present invention is explained in detail in the following by
referring to Examples, Experimental Examples and Preparation
Examples. However, the examples do not limit the present invention
and the present invention can be modified within the scope of the
present invention.
The "room temperature" in the following Examples is generally about
10.degree. C. to about 35.degree. C. The ratio for a mixed solvent
is, unless otherwise specified, a volume mixing ratio and % means
wt % unless otherwise specified.
In silica gel column chromatography, the indication of NH means use
of aminopropylsilane-bonded silica gel. In HPLC (high performance
liquid chromatography), the indication of C18 means use of
octadecyl-bonded silica gel. The ratio of elution solvents is,
unless otherwise specified, a volume mixing ratio.
In the following Examples, the following abbreviations are
used.
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
NMP: N-methylpyrrolidone
DMSO: dimethyl sulfoxide
ESI: electrospray ionization method
API: atmospheric chemical ionization method
[M+H].sup.+: molecular ion peak
TFA: trifluoroacetic acid
M: molar concentration
N: normal concentration
WSC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride
HOBt: 1-hydroxybenzotriazole monohydrate
Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)dipalladium(0)
Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
MCPBA: m-chloroperbenzoic acid
HPLC: high performance liquid chromatography
.sup.1H NMR (proton nuclear magnetic resonance spectrum) was
measured by Fourier-transform type NMR. For the analysis,
ACD/SpecManager (trade name) and the like were used. Very mild
peaks showing protons of hydroxyl group, amino group and the like
are not described.
MS (mass spectrum) was measured by LC/MS (liquid chromatography
mass spectrometer).
As the ionization method, ESI (ElectroSpray Ionization) method, or
APCI (Atomospheric Pressure Chemical Ionization) method was used.
The data shows Found. Generally, molecular ion peaks are observed.
However, when a compound having a tert-butoxycarbonyl group (-Boc)
is used, a peak free of a tert-butoxycarbonyl group or a tert-butyl
group may be observed as a fragment ion. In addition, when a
compound having a hydroxyl group (--OH) is used, a peak free of
H.sub.2O may be observed as a fragment ion. In the case of a salt,
generally, a molecular ion peak or a fragment ion peak of a free
form is observed.
Example 1 and Example 2
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(3-methyl-1-phenyl-1H-p-
yrazol-5-yl)pyridazin-4(1H)-one (Example 1)
5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-(3-methyl-1-phenyl-1H--
pyrazol-5-yl)pyridazin-4(1H)-one (Example 2)
A mixture of
3-acetyl-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)--
one (300 mg), N,N-dimethylacetamide dimethyl acetal (3 mL) and
acetonitrile (3 mL) was stirred at 80.degree. C. for 12 hr, and the
solvent was evaporated under reduced pressure. The residue was
dissolved in acetic acid (5 mL), phenylhydrazine (98.8 mg) was
added thereto at room temperature. The reaction mixture was stirred
at 80.degree. C. for 3 hr, and the solvent was evaporated under
reduced pressure. The mixture was treated with 1M hydrochloric
acid, and the residue was extracted with ethyl acetate. The extract
was dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/methanol) to give a
mixture containing
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(3-methyl-1-phenyl-1H--
pyrazol-5-yl)pyridazin-4(1H)-one (69 mg) and
5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-(3-methyl-1-phenyl-1H-
-pyrazol-5-yl)pyridazin-4(1H)-one. The obtained mixture was
purified by preparative HPLC to give
5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-(3-methyl-1-phenyl-1H-
-pyrazol-5-yl)pyridazin-4(1H)-one (28 mg).
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(3-methyl-1-phenyl-1H-p-
yrazol-5-yl)pyridazin-4(1H)-one
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (3H, s), 3.78 (3H,
s), 6.59-6.66 (1H, m), 6.79 (1H, s), 7.08-7.21 (1H, m), 7.25-7.49
(5H, m), 7.74 (1H, d, J=8.7 Hz), 7.83 (1H, d, J=1.5 Hz), 7.91-8.04
(1H, m), 8.52 (1H, d, J=1.9 Hz), 8.66 (1H, d, J=2.7 Hz).
5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-(3-methyl-1-phenyl-1H--
pyrazol-5-yl)pyridazin-4(1H)-one
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.2.29 (3H, s), 3.76 (3H,
s), 3.91 (3H, s), 6.60 (1H, s), 6.75 (1H, s), 6.93 (1H, d, J=8.7
Hz), 7.20-7.49 (6H, m), 7.64 (1H, d, J=1.9 Hz), 7.80 (1H, s), 8.38
(1H, s), 8.66 (1H, d, J=2.7 Hz).
Example 3
3-[1-(3-chloro-2-fluorophenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyrazol--
1-yl)phenyl]-5-methoxypyridazin-4(1H)-one
A)
3-[3-(dimethylamino)prop-2-enoyl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl-
]-5-methoxypyridazin-4(1H)-one
A mixture of
3-acetyl-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)--
one (600 mg), N,N-dimethylformamide dimethyl acetal (3 mL) and
acetonitrile (3 mL) was stirred at 80.degree. C. for 12 hr, allowed
to be cooled to room temperature, and stirred for 12 hr. The
precipitate was collected by filtration, and washed with
diisopropyl ether to give the title compound (600 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.82 (3H, s), 3.09 (3H,
s), 3.79 (3H, s), 5.25 (1H, brs), 6.64 (1H, dd, J=2.5, 1.8 Hz),
7.51 (1H, brs), 7.79-7.95 (3H, m), 7.99-8.10 (1H, m), 8.50 (1H, d,
J=1.8 Hz), 8.68 (1H, d, J=2.5 Hz).
B)
3-[1-(3-chloro-2-fluorophenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyraz-
ol-1-yl)phenyl]-5-methoxypyridazin-4 (H)-one
To a solution of
3-[3-(dimethylamino)prop-2-enoyl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]--
5-methoxypyridazin-4(1H)-one (200 mg) in TFA/ethanol (5/95, 8 mL)
was added (3-chloro-2-fluorophenyl)hydrazine hydrochloride (98.8
mg) under ice-cooling. The reaction mixture was stirred at room
temperature for 3 hr, water was added thereto, and the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/methanol) to give the title compound
(97 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.80 (3H, s), 6.57-6.71
(1H, m), 7.12-7.22 (1H, m), 7.23-7.32 (1H, m), 7.38-7.49 (2H, m),
7.55-7.69 (1H, m), 7.72-7.81 (1H, m), 7.81-8.01 (3H, m), 8.50 (1H,
d, J=1.9 Hz), 8.67 (1H, d, J=2.6 Hz)
Example 4
3-[1-(5-chloro-2-fluorophenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyrazol--
1-yl)phenyl]-5-methoxypyridazin-4 (H)-one
To a solution of
3-[3-(dimethylamino)prop-2-enoyl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]--
5-methoxypyridazin-4 (H)-one (200 mg) in TFA/ethanol (5/95, 8 mL)
was added (5-chloro-2-fluorophenyl)hydrazine hydrochloride (88.8
mg) under ice-cooling. The reaction mixture was stirred at room
temperature for 3 hr, water was added thereto, and the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/methanol) to give the title compound
(98 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.80 (3H, s), 6.52-6.71
(1H, m), 7.10-7.26 (1H, m), 7.27-7.41 (2H, m), 7.45-7.54 (1H, m),
7.60-7.68 (1H, m), 7.74-7.81 (1H, m), 7.82-7.90 (2H, m), 7.92-8.00
(1H, m), 8.51 (1H, d, J=1.9 Hz), 8.67 (1H, d, J=2.6 Hz).
Example 5
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-{1-[3-(trifluoromethyl)-
phenyl]-1H-pyrazol-5-yl}pyridazin-4 (H)-one
To a solution of
3-[3-(dimethylamino)prop-2-enoyl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]--
5-methoxypyridazin-4 (H)-one (200 mg) in TFA/EtOH (5/95, 8 mL) was
added [3-(trifluoromethyl)phenyl]hydrazine (96.5 mg) under
ice-cooling. The reaction mixture was stirred at room temperature
for 3 hr, water was added thereto, and the mixture was extracted
with ethyl acetate. The extract was dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/methanol) to give the title compound (185 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.79 (3H, s), 6.63 (1H,
s), 7.11 (1H, s), 7.30-7.44 (1H, m), 7.56-7.82 (5H, m), 7.80-7.92
(2H, m), 7.93-8.04 (1H, m), 8.56 (1H, s), 8.66 (1H, d, J=2.3
Hz).
Example 6
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-[1-(2,2,2-trifluoroethy-
l)-1H-pyrazol-5-yl]pyridazin-4(1H)-one
To a suspension of
3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-y-
l)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added
dropwise a solution of 2,2,2-trifluoroethylhydrazine (0.0483 mL)
and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was stirred
at room temperature for 48 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (ethyl acetate/hexane) to give
the title compound (170 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.86 (3H, s), 5.36 (2H,
q, J=8.9 Hz), 6.65 (1H, d, J=2.6 Hz), 7.17 (1H, d, J=1.9 Hz), 7.71
(1H, d, J=1.9 Hz), 7.86 (1H, d, J=1.5 Hz), 7.89-7.99 (2H, m), 8.08
(1H, d, J=1.9 Hz), 8.64 (1H, s), 8.70 (1H, d, J=2.6 Hz)
mp 185-187.degree. C.
Anal. Calcd for C.sub.19H.sub.14F.sub.4N.sub.6O.sub.2: C, 52.54; H,
3.25; N, 19.35. Found: C, 52.49; H, 3.25; N, 19.32.
Example 7
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-{1-[3-(trifluoromethoxy-
)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one
A) [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride
3-(Trifluoromethoxy)aniline (3.68 ml) was dissolved in 6 M
hydrochloric acid (71 ml), and an aqueous solution (4.7 ml) of
sodium nitrite (2.08 g) was added dropwise over 20 min at
-5.degree. C. Tin (II) chloride (1.954 ml) was dissolved in 6 M
hydrochloric acid (25 ml), and the solution was cooled to
-5.degree. C., and added quickly to the above-mentioned reaction
mixture at -5.degree. C. The mixture was stirred at -5.degree. C.
for 2 hr, and the precipitated solid was collected by filtration,
washed with 0.1M hydrochloric acid, and dried under reduced
pressure to give the title compound (2.72 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.81-7.03 (3H, m), 7.41
(1H, t, J=8.3 Hz), 8.64 (1H, br. s.), 10.35 (2H, br. s.)
B)
1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-{1-[3-(trifluorometh-
oxy)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one
To a suspension of
3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-y-
l)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added
dropwise a solution of [3-(trifluoromethoxy)phenyl]hydrazine
hydrochloride (139 mg) and TFA (0.2 mL) in ethanol (2.0 mL), and
the mixture was so stirred at room temperature for 24 hr. To the
reaction mixture was added an ethanol solution (0.3 ml) of
[3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (16.7 mg), and
the mixture was stirred at room temperature for 24 hr. The
precipitated solid was collected by filtration. The mother liquor
was concentrated, and the precipitated solid was collected by
filtration. The solid was combined with the previously obtained
solid, and recrystallized from acetone/water to give the title
compound (96.1 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.79 (3H, s), 6.64 (1H,
d, J=2.6 Hz), 7.03 (1H, d, J=1.9 Hz), 7.27-7.49 (4H, m), 7.57 (1H,
t, J=8.1 Hz), 7.74-7.88 (3H, m), 7.99 (1H, dd, J=12.1, 2.3 Hz),
8.57 (1H, d, J=1.9 Hz), 8.66 (1H, d, J=2.6 Hz)
mp 148-150.degree. C.
Anal. Calcd for C.sub.24H.sub.16F.sub.4N.sub.6O.sub.3-0.5H.sub.2O:
C, 55.28; H, 3.29; N, 16.11. Found: C, 55.25; H, 3.07; N,
16.05.
Example 8
5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-{1-[3-(trifluoromethyl-
)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one
A)
3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazol--
1-yl)phenyl]pyridazin-4(1H)-one
A mixture of
3-acetyl-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-
-one (264 mg), N,N-dimethylformamide dimethyl acetal (1.5 mL) and
acetonitrile (1.5 mL) was heated under reflux for 3 hr. The
reaction mixture was concentrated under reduced pressure, and the
residue was crystallized from ethanol to give the title compound
(274 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.90 (3H, s), 3.12 (3H,
s), 3.89 (3H, s), 3.97 (3H, s), 5.89 (1H, brs), 6.52 (1H, dd,
J=2.6, 1.9 Hz), 7.26 (1H, dd, J=8.3, 2.3 Hz), 7.59 (1H, d, J=1.9
Hz), 7.63 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=1.9 Hz), 7.79 (1H,
brs), 7.82 (1H, s), 7.98 (1H, d, J=2.3 Hz).
B)
5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-{1-[3-(trifluoromet-
hyl)phenyl]-1H-pyrazol-5-yl}pyridazin-4(1H)-one
To a suspension of
3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1--
yl)phenyl]pyridazin-4(1H)-one (136 mg) in ethanol (1.5 mL) was
added dropwise a solution of 3-(trifluoromethyl)phenylhydrazine
(0.049 mL) and TFA (0.15 mL) in ethanol (1.5 mL), and the mixture
was stirred at room temperature for 3 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (NH, ethyl acetate), and
recrystallized from ethanol/water to give the title compound (123
mg).
mp 215-217.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.89 (3H, s), 3.93 (3H,
s), 6.53 (1H, dd, J=2.6, 1.9 Hz), 6.62 (1H, d, J=8.7 Hz), 7.03 (1H,
dd, J=8.7, 2.3 Hz), 7.30 (1H, d, J=1.9 Hz), 7.48-7.53 (2H, m),
7.57-7.62 (2H, m), 7.67-7.68 (1H, m), 7.76 (1H, d, J=1.5 Hz), 7.80
(1H, d, J=1.9 Hz), 7.82 (1H, s), 7.93 (1H, d, J=2.3 Hz).
Anal. Calcd for C.sub.25H.sub.19F.sub.3N.sub.6O.sub.3: C, 59.06; H,
3.77; N, 16.53. Found: C, 58.97; H, 3.85; N, 16.40.
Example 9
3-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazo-
l-1-yl)phenyl]pyridazin-4(1H)-one
To a suspension of
3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1--
yl)phenyl]pyridazin-4(1H)-one (136 mg) in ethanol (1.5 mL) was
added dropwise a solution of 3-chlorophenylhydrazine hydrochloride
(67.7 mg) and TFA (0.15 mL) in ethanol (1.5 mL), and the mixture
was stirred at room temperature for 5 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (NH, ethyl acetate),
crystallized from ethyl acetate, and recrystallized from
ethanol/water to give the title compound (68.0 mg).
mp 167-168.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta. 3.90 (3H, s), 3.95 (3H, s), 6.53
(1H, dd, J=2.6, 1.9 Hz), 6.68 (1H, d, J=8.7 Hz), 7.08 (1H, dd,
J=8.7, 2.3 Hz), 7.27-7.36 (4H, m), 7.44-7.45 (1H, m), 7.53 (1H, d,
J=2.3 Hz), 7.76 (1H, d, J=1.9 Hz), 7.77 (1H, d, J=1.9 Hz), 7.84
(1H, s), 7.96 (1H, d, J=2.6 Hz).
Anal. Calcd for C.sub.24H.sub.19ClN.sub.6O.sub.3: C, 60.70; H,
4.03; N, 17.70. Found: C, 60.73; H, 4.08; N, 17.58.
Example 10
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-3-(1-phe-
nyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
A) 4-bromo-2-(tert-butoxy)-1-nitrobenzene
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25.2 g) in THF
(250 mL) was added potassium tert-butoxide (25.3 g) portionwise at
0.degree. C., and the mixture was stirred at 0.degree. C. for 30
min. The reaction mixture was poured into water, and the mixture
was extracted with ethyl acetate. The extract was washed with water
and saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate) to give the
title compound (28.6 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.44 (9H, s), 7.26 (1H,
dd, J=8.7, 2.3 Hz), 7.38 (1H, d, J=2.3 Hz), 7.62 (1H, d, J=8.7
Hz).
B) 1-(3-tert-butoxy-4-nitrophenyl)-3,4-difluoro-1H-pyrrole
A suspension of 4-bromo-2-(tert-butoxy)-1-nitrobenzene (13.7 g),
3,3,4,4-tetrafluoropyrrolidine hydrochloride (9.87 g),
Pd.sub.2(dba).sub.3 (0.916 g), Xantphos (2.31 g) and sodium
tert-butoxide (19.2 g) in 1,4-dioxane (150 mL) was stirred at
90.degree. C. for 4 hr under an argon atmosphere. The reaction
mixture was poured into water, and the mixture was extracted with
ethyl acetate. The extract was washed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, hexane/ethyl acetate), and recrystallized from
hexane/ethyl acetate to give the title compound (8.35 g).
.sup.1H NMR (300 MHZ, CDCl.sub.3) .delta. 1.47 (9H, s), 6.72-6.82
(2H, m), 7.00 (1H, dd, J=8.7, 2.6 Hz), 7.04 (1H, d, J=2.6 Hz), 7.88
(1H, d, J=8.7 Hz).
C) 5-(3,4-difluoro-1H-pyrrol-1-yl)-2-nitrophenol
A mixture of
1-(3-tert-butoxy-4-nitrophenyl)-3,4-difluoro-1H-pyrrole (8.30 g),
TFA (30 mL) and THF (60 mL) was heated under reflux for 3 hr. The
reaction mixture was concentrated under reduced pressure, and the
residue was washed with hexane/ethyl acetate (10/1) to give the
title compound (6.43 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.80-6.91 (3H, m), 6.98
(1H, d, J=2.6 Hz), 8.18 (1H, d, J=9.4 Hz), 10.85 (1H, s).
D) 1-[3-(benzyloxy)-4-nitrophenyl]-3,4-difluoro-1H-pyrrole
A suspension of 5-(3,4-difluoro-1H-pyrrol-1-yl)-2-nitrophenol (6.39
g), benzyl bromide (3.48 mL) and potassium carbonate (5.51 g) in
DMF (60 mL) was stirred at room temperature overnight. The reaction
mixture was poured into water, and the mixture was extracted with
ethyl acetate. The extract was washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was recrystallized from
hexane/ethyl acetate to give the title compound (8.57 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.30 (2H, s), 6.67-6.77
(2H, m), 6.88-6.92 (2H, m), 7.33-7.51 (5H, m), 8.02 (1H, d, J=8.3
Hz).
E) 2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)aniline
To a mixture of zinc (33.7 g), THF (40 mL) and acetic acid (80 mL)
was added dropwise a mixture of
1-[3-(benzyloxy)-4-nitrophenyl]-3,4-difluoro-1H-pyrrole (8.52 g),
THF (80 mL) and acetic acid (40 mL) at 0.degree. C., and the
mixture was stirred at 0.degree. C. for 15 min. The reaction
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (NH, hexane/ethyl acetate), and recrystallized from
hexane/ethyl acetate to give the title compound (7.53 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.86 (2H, s), 5.10 (2H,
s), 6.50-6.60 (2H, m), 6.69-6.76 (3H, m), 7.33-7.46 (5H, m).
F) methyl
2-{[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]hydrazon-
o}-4-methoxy-3-oxobutanoate
To a mixture of
2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)aniline (7.51 g) and
6M hydrochloric acid (50 mL) was added dropwise a solution of
sodium nitrite (3.45 g) in water (10 mL) at 0.degree. C., and the
mixture was stirred for 15 min. The reaction mixture was added to a
suspension (cooled to 0.degree. C.) of 4-methyl methoxyacetoacetate
(3.24 mL) and sodium acetate (24.6 g) in methanol (50 mL). The
reaction mixture was stirred for 15 min, and poured into water, and
the mixture was extracted with ethyl acetate. The extract was
washed with saturated aqueous sodium hydrogen carbonate solution
and saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was washed with
hexane/ethyl acetate, and recrystallized from hexane/THF to give
the title compound (4.87 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.51 (3H, s), 3.90 (3H,
s), 4.68 (2H, s), 5.27 (2H, s), 6.59-6.69 (2H, m), 6.87 (1H, d,
J=2.3 Hz), 6.94 (1H, dd, J=8.7, 2.3 Hz), 7.34-7.52 (5H, m), 7.61
(1H, d, J=8.7 Hz), 13.27 (1H, s).
G) methyl
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methox-
y-4-oxo-1,4-dihydropyridazine-3-carboxylate
A mixture of methyl
2-{[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]hydrazono}-4-meth-
oxy-3-oxobutanoate (4.85 g) and N,N-dimethylformamide dimethyl
acetal (100 mL) was heated under reflux for 3 hr. The mixture was
allowed to be cooled to room temperature, and the precipitate was
collected by filtration, and recrystallized from methanol to give
the title compound (4.57 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.64 (3H, s), 3.97 (3H,
s), 5.17 (2H, s), 6.69-6.79 (2H, m), 6.99-7.03 (2H, m), 7.32-7.43
(5H, m), 7.59-7.62 (1H, m), 7.80 (1H, s).
H)
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-4-oxo-
-1,4-dihydropyridazine-3-carboxylic acid
A mixture of methyl
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-4-oxo-1-
,4-dihydropyridazine-3-carboxylate (4.54 g), 1M aqueous sodium
hydroxide solution (15 mL), THF (30 mL) and methanol (30 mL) was
stirred at room temperature for 30 min. The reaction mixture was
neutralized with 1M hydrochloric acid, and the precipitate was
collected by filtration, and washed with water to give the title
compound (0.5 THF solvate, 4.70 g).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.3.78 (3H, s), 5.32 (2H,
s), 7.31-7.45 (6H, m), 7.59 (1H, d, J=2.3 Hz), 7.69-7.71 (3H, m),
8.89 (1H, s), 15.18 (1H, brs).
I)
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-N,5-dimethoxy-N-
-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
A suspension of
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-4-oxo-1-
,4-dihydropyridazine-3-carboxylic acid (0.5 THF solvate, 4.67 g),
N,O-dimethylhydroxylamine hydrochloride (1.11 g), WSC (2.19 g),
HOBt (1.54 g) and triethylamine (1.59 mL) in DMF (75 mL) was
stirred at room temperature for 6 hr. The reaction mixture was
poured into water, and the mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (NH, THF), and recrystallized from hexane/THF to
give the title compound (4.51 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.38 (3H, s), 3.62 (3H,
s), 3.67 (3H, s), 5.17 (2H, s), 6.69-6.79 (2H, m), 6.97-7.01 (2H,
m), 7.32-7.44 (5H, m), 7.59-7.64 (1H, m), 7.86 (1H, s).
J)
3-acetyl-1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-meth-
oxypyridazin-4(1H)-one
To a solution of
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-N,5-dimethoxy-N-m-
ethyl-4-oxo-, 4-dihydropyridazine-3-carboxamide (4.47 g) in THF
(270 mL) was added dropwise 1M methylmagnesium bromide THF solution
(27 mL) at -78.degree. C., and the mixture was stirred for 15 min.
To the reaction mixture was added 1M hydrochloric acid, and the
mixture was extracted with ethyl acetate. The extract was washed
with water and saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
washed with THF, and recrystallized from methanol to give the title
compound (3.75 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.68 (3H, s), 3.63 (3H,
s), 5.18 (2H, s), 6.71-6.81 (2H, m), 7.00-7.04 (2H, m), 7.32-7.44
(5H, m), 7.59-7.62 (1H, m), 7.80 (1H, s).
K)
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-3-[3-(dimethyla-
mino)prop-2-enoyl]-5-methoxypyridazin-4(1H)-one
A mixture of
3-acetyl-1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methox-
ypyridazin-4(1H)-one (3.70 g), N,N-dimethylformamide dimethyl
acetal (40 mL) and acetonitrile (40 mL) was heated under reflux for
6 hr. The reaction mixture was concentrated under reduced pressure,
and the residue was crystallized from ethanol to give the title
compound (3.85 g).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.78 (3H, brs), 3.05
(3H, brs), 3.65 (3H, s), 5.26 (1H, brs), 5.31 (2H, s), 7.30-7.47
(6H, m), 7.54 (1H, d, J=2.3 Hz), 7.61 (1H, d, J=8.7 Hz), 7.66 (2H,
d, J=1.5 Hz), 8.40 (1H, s).
L)
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-3-(1--
phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
A solution of
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-3-[3-(dimethylami-
no)prop-2-enoyl]-5-methoxypyridazin-4(1H)-one (3.80 g) and
phenylhydrazine (1.48 mL) in acetic acid (30 mL) was heated under
reflux for 2 hr. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by silica gel column
chromatography (NH, ethyl acetate), crystallized from hexane/ethyl
acetate, and recrystallized from dimethylsulfoxide/ethanol to give
the title compound (3.29 g).
mp 221-223.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.57 (3H, s), 5.10 (2H,
s), 6.31 (1H, d, J=8.7 Hz), 6.65-6.75 (3H, m), 6.92 (1H, d, J=2.3
Hz), 7.27-7.46 (11H, m), 7.78 (1H, d, J=2.3 Hz), 7.88 (1H, s).
Anal. Calcd for C.sub.31H.sub.23F.sub.2N.sub.5O.sub.3: C, 67.51; H,
4.20; N, 12.70. Found: C, 67.48; H, 4.27; N, 12.62.
Example 11
1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl--
1H-pyrazol-5-yl)pyridazin-4(1H)-one
A suspension of
1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-3-(1-ph-
enyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (3.20 g) and 10% palladium
on carbon (containing water (50%), 3.20 g) in acetic acid (100 mL)
was stirred at room temperature for 3 hr under a hydrogen
atmosphere. The palladium on carbon was removed by filtration, and
the filtrate was concentrated under reduced pressure. The residue
was purified by SFC (column: CHIRALPAK ADH (trade name), 20
mmID.times.250 mL, manufactured by DAICEL CHEMICAL INDUSTRIES,
LTD., mobile phase: carbon
dioxide/2-propanol/acetonitrile=700/150/150 (v/v/v)), and the
obtained fraction was concentrated under reduced pressure. The
residue was recrystallized from acetone to give the title compound
(1.24 g).
mp 241-243.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.75 (3H, s), 6.80 (1H,
d, J=8.7 Hz), 6.90-6.99 (2H, m), 7.02 (1H, d, J=2.3 Hz), 7.29-7.49
(7H, m), 7.78 (1H, d, J=1.9 Hz), 8.35 (1H, s), 10.90 (1H, brs).
Anal. Calcd for
C.sub.24H.sub.17F.sub.2N.sub.5O.sub.3-0.5C.sub.3H.sub.4O: C, 62.45;
H, 4.11; N, 14.28. Found: C, 62.33; H, 4.06; N, 14.39.
Example 12
1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-methoxyphenyl]-5-methoxy-3-(1-phenyl--
1H-pyrazol-5-yl)pyridazin-4(1H)-one
A suspension of
1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-
-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), iodomethane (0.0375
mL) and potassium carbonate (138 mg) in DMF (2.5 mL) was stirred at
room temperature overnight. The reaction mixture was poured into
water, and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (NH, THF),
and recrystallized from methanol/water to give the title compound
(232 mg).
mp 206-207.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.89 (6H, s), 6.36 (1H,
d, J=8.7 Hz), 6.65-6.77 (3H, m), 6.81 (1H, d, J=2.3 Hz), 7.25 (1H,
d, J=1.9 Hz), 7.35-7.46 (5H, m), 7.77 (1H, d, J=1.9 Hz), 7.81 (1H,
s).
Anal. Calcd for C.sub.25H.sub.19F.sub.2N.sub.5O.sub.3: C, 63.15; H,
4.03; N, 14.73. Found: C, 62.96; H, 3.98; N, 14.66.
Example 13
1-[2-(difluoromethoxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-3--
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
A mixture of
1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-
-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), sodium
chlorodifluoroacetate (152 mg), potassium carbonate (104 mg), DMF
(2.5 mL) and water (0.5 mL) was heated under reflux overnight. The
reaction mixture was poured into water, and the mixture was
extracted with ethyl acetate. The extract was washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, ethyl acetate), and crystallized from
hexane/ethyl acetate to give the title compound (193 mg).
mp 168-170.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.89 (3H, s), 6.41 (1H,
t, J=72.0 Hz), 6.56 (1H, d, J=8.7 Hz), 6.69-6.79 (2H, m), 6.99 (1H,
dd, J=8.7, 2.6 Hz), 7.12 (1H, d, J=2.6 Hz), 7.25 (1H, d, J=1.9 Hz),
7.34-7.46 (5H, m), 7.74 (1H, s), 7.78 (1H, d, J=1.9 Hz).
Anal. Calcd for C.sub.25H.sub.17F.sub.4N.sub.5O.sub.3: C, 58.71; H,
3.35; N, 13.69. Found: C, 58.68; H, 3.41; N, 13.55.
Example 14
1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl]-5-meth-
oxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
A suspension of
1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-
-1H-pyrazol-5-yl)pyridazin-4(1H)-one (138 mg), 2,2,2-trifluoroethyl
trifluoromethanesulfonate (104 mg) and potassium carbonate (82 mg)
in DMF (1.5 mL) was stirred at room temperature for 30 min. The
reaction mixture was poured into water, and the mixture was
extracted with ethyl acetate. The extract was washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (NH, THF), and crystallized from methanol to
give the title compound (131 mg).
mp 220-222.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.86 (3H, s), 4.41 (2H,
q, J=7.9 Hz), 6.37-6.41 (1H, m), 6.67-6.80 (4H, m), 7.28 (1H, d,
J=1.9 Hz), 7.35-7.47 (5H, m), 7.78 (1H, d, J=1.9 Hz), 7.83 (1H,
s).
Anal. Calcd for C.sub.26H.sub.18F.sub.5N.sub.5O.sub.3: C, 57.46; H,
3.34; N, 12.89. Found: C, 57.38; H, 3.38; N, 12.83.
Example 15
5-methoxy-1-[2-methoxy-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)phenyl]-3-(1--
phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
A)
3-acetyl-1-(4-iodo-2-methoxyphenyl)-5-methoxypyridazin-4(1H)-one
To a solution of
1-(4-iodo-2-methoxyphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyrida-
zine-3-carboxamide (8.90 g) in THF (150 mL) was added dropwise 1M
methylmagnesium bromide THF solution (30 mL) at -78.degree. C., and
the mixture was stirred for 20 min. To the reaction mixture was
added 1M hydrochloric acid, and the mixture was extracted with
ethyl acetate. The extract was washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was washed with ethyl acetate,
and recrystallized from methanol/water to give the title compound
(5.12 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.66 (3H, s), 3.87 (3H,
s), 3.90 (3H, s), 7.21 (1H, d, J=8.3 Hz), 7.40 (1H, d, J=1.9 Hz),
7.47 (1H, dd, J=8.3, 1.9 Hz), 7.71 (1H, s).
B)
1-(4-iodo-2-methoxyphenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyrida-
zin-4(1H)-one
A mixture of
3-acetyl-1-(4-iodo-2-methoxyphenyl)-5-methoxypyridazin-4(1H)-one
(2.00 g), N,N-dimethylformamide dimethyl acetal (10 mL) and
acetonitrile (10 mL) was heated under reflux for 8 hr. The mixture
was allowed to be cooled to room temperature, and concentrated
under reduced pressure.
To a solution of the obtained residue in ethanol (20 mL) was added
dropwise a solution of phenylhydrazine (0.541 mL) and TFA (0.743
mL) in ethanol (5 mL) at 0.degree. C., and the mixture was stirred
at room temperature for 3 hr. The reaction mixture was concentrated
under reduced pressure, and the residue was purified by silica gel
column chromatography (ethyl acetate), and recrystallized from
ethanol/water to give the title compound (1.36 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.84 (3H, s), 3.88 (3H,
s), 5.98 (1H, d, J=8.3 Hz), 7.13 (1H, dd, J=8.3, 1.9 Hz), 7.25-7.28
(2H, m), 7.34-7.45 (5H, m), 7.77 (1H, d, J=1.9 Hz), 7.79 (1H,
s).
C)
5-methoxy-1-[2-methoxy-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)phenyl]-3--
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4 (H)-one
A suspension of
1-(4-iodo-2-methoxyphenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazi-
n-4(1H)-one (186 mg), 3,3,4,4-tetrafluoropyrrolidine hydrochloride
(80.0 mg), Pd.sub.2(dba).sub.3 (6.8 mg), Xantphos (17.4 mg) and
sodium tert-butoxide (93.0 mg) in 1,4-dioxane (2 mL) was stirred at
90.degree. C. for 30 min under an argon atmosphere. The reaction
mixture was poured into water, and the mixture was extracted with
ethyl acetate. The extract was washed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, ethyl acetate), and purified by HPLC (L-Column
2 ODS, mobile phase: water/acetonitrile (containing 5% ammonium
acetate)). The obtained fraction was concentrated under reduced
pressure, and to the residue was added saturated aqueous sodium
hydrogen carbonate solution, and the mixture was extracted with
ethyl acetate. The extract was washed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was crystallized from methanol/water to give
the title compound (41.1 mg).
mp 209-213.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.76-3.93 (10H, m), 5.91
(1H, dd, J=8.7, 2.6 Hz), 6.00 (1H, d, J=2.6 Hz), 6.31 (1H, d, J=8.7
Hz), 7.19 (1H, d, J=1.9 Hz), 7.31-7.45 (5H, m), 7.73 (1H, s), 7.76
(1H, d, J=1.9 Hz).
Anal. Calcd for C.sub.25H.sub.21F.sub.4N.sub.5O.sub.3: C, 58.25; H,
4.11; N, 13.59. Found: C, 58.24; H, 4.10; N, 13.62.
Example 16
4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl-
]-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one
A) 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one
To a solution of 4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
(4.1 g) in concentrated sulfuric acid (60 mL) was added dropwise a
mixture of fuming nitric acid (0.99 mL) and concentrated sulfuric
acid (10 mL) over 30 min at -30.degree. C. The reaction mixture was
stirred between -30.degree. C. to 0.degree. C. for 30 min, and
poured into ice. The resulting solid was collected by filtration,
washed with water, and dissolved in ethyl acetate. The obtained
solution was washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(2.2 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.57 (6H, s), 6.84 (1H,
d, J=8.7 Hz), 8.10 (1H, dd, J=8.7, 7.5 Hz), 8.76 (1H, brs).
B) 5-amino-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
A suspension of
4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (3.5 g),
palladium on carbon (containing water (50%), 2.0 g) in methanol
(150 mL) was stirred at room temperature for 3 hr under a hydrogen
atmosphere. The palladium on carbon was removed by filtration, and
the filtrate was concentrated under reduced pressure to give the
title compound (2.9 g).
MS (API+), found: 195.1
C) methyl
(2E)-2-[(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)h-
ydrazono]-4-methoxy-3-oxobutanoate
By a method similar to Step F of Example 10, and using
5-amino-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one, the title
compound was obtained.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.54 (6H, s), 3.51 (3H,
s), 3.88 (3H.times.1/2, s), 3.93 (3H.times.1/2, s), 4.66
(2H.times.1/2, s), 4.69 (2H.times.1/2, s), 6.78 (1H, d, J=8.3 Hz),
7.48 (1H.times.1/2, t, J=7.9 Hz), 7.72 (1H.times.1/2, t, J=8.1 Hz),
7.88 (1H.times.1/2, brs), 7.92 (1H.times.1/2, brs), 13.18
(1H.times.1/2, s), 15.12 (1H.times.1/2, s).
D) methyl
1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-m-
ethoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate
By a method similar to Step G of Example 10, and using methyl
(2E)-2-[(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)hydrazono]-
-4-methoxy-3-oxobutanoate, the title compound was obtained.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.53 (6H, s), 3.27 (3H,
s), 3.93 (3H, s), 3.98 (3H, s), 6.78 (1H, d, J=8.3 Hz), 7.52 (1H,
dd, J=8.3, 7.5 Hz), 7.72 (1H, d, J=2.3 Hz).
E)
1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy--
4-oxo-1,4-dihydropyridazine-3-carboxylic acid
By a method similar to Step H of Example 10, and using methyl
1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4--
oxo-1,4-dihydropyridazine-3-carboxylate, the title compound was
obtained.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.43 (6H, s), 3.22 (3H,
s), 3.90 (3H, s), 7.15 (1H, d, J=8.3 Hz), 7.75 (1H, t, J=8.1 Hz),
8.88 (1H, s).
F)
1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-N,5-dimeth-
oxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide
By a method similar to Step I of Example 10, and using
1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4--
oxo-1,4-dihydropyridazine-3-carboxylic acid, the title compound was
obtained.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.52 (6H, s), 3.26 (3H,
s), 3.39 (3H, s), 3.73 (3H, s), 3.93 (3H, s), 6.76 (1H, d, J=8.3
Hz), 7.52 (1H, t, J=7.9 Hz), 7.75 (1H, d, J=1.9 Hz)
G)
5-(3-acetyl-5-methoxy-4-oxopyridazin-1(4H)-yl)-4-fluoro-1,3,3-trimethyl-
-1,3-dihydro-2H-indol-2-one
By a method similar to Step J of Example 10, and using
1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-N,5-dimethox-
y-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide, the title
compound was obtained.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.53 (6H, s), 2.69 (3H,
s), 3.27 (3H, s), 3.93 (3H, s), 6.80 (1H, d, J=8.3 Hz), 7.53 (1H,
t, J=7.9 Hz), 7.72 (1H, d, J=2.3 Hz).
H)
4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-
-yl]-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one
By a method similar to Step B of Example 15, and using
5-(3-acetyl-5-methoxy-4-oxopyridazin-1(4H)-yl)-4-fluoro-1,3,3-trimethyl-1-
,3-dihydro-2H-indol-2-one, the title compound was obtained.
MS (API+), found: 460.1
Example 17
5-{3-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-5-methoxy-4-oxopyridazin-1(4H)-y-
l}-4-fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one
By a method similar to Step B of Example 15, and using
5-(3-acetyl-5-methoxy-4-oxopyridazin-1(4H)-yl)-4-fluoro-1,3,3-trimethyl-1-
,3-dihydro-2H-indol-2-one and 3-chlorophenylhydrazine, the title
compound was obtained.
MS (API+), found: 494.2
Example 18
4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl-
]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-indol-2-one
A) 1-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-ol
To an THF solution (450 ml) of 1-phenylpyrazole (15 g) was added
1.6M butyllithium/hexane solution at -78.degree. C., and the
mixture was stirred at -78.degree. C. for 1 hr. To the reaction
mixture was added 2-(methoxymethyl)oxirane (27.8 ml) at -78.degree.
C., and the mixture was allowed to be warmed to room temperature,
and stirred for 1 hr. To the reaction mixture was added 1N
hydrochloric acid, the mixture was extracted with ethyl acetate,
and the extract was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (12.2 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.33 (1H, d, J=4.1 Hz),
2.88 (2H, dd, J=6.6, 3.2 Hz), 3.19-3.28 (1H, m), 3.33 (3H, s),
3.34-3.40 (1H, m), 3.94-4.06 (1H, m, J=10.0, 6.8, 3.4, 3.4 Hz),
6.30-6.38 (1H, m), 7.34-7.53 (5H, m), 7.63 (1H, s).
B) 1-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-one
To a THF solution (100 ml) of DMSO (14.2 ml) was added dropwise
trifluoroacetic anhydride over 15 min at -42.degree. C., and the
mixture was stirred at -42.degree. C. for 15 min. To the reaction
mixture was added dropwise an THF solution (66 ml) of
1-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-ol (9.3 g) over 1 hr
at -42.degree. C., and the mixture was stirred at 0.degree. C. for
15 min. To the reaction mixture was added dropwise triethylamine
(22.3 ml) over 15 min at 0.degree. C., and the mixture was stirred
at 0.degree. C. for 1 hr. To the reaction mixture was added 10%
aqueous sodium carbonate solution, and the mixture was extracted
with ethyl acetate, and the extract was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(4.11 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.33 (3H, s), 3.88 (2H,
s), 3.95 (2H, s), 6.34 (1H, d, J=1.9 Hz), 7.35-7.52 (5H, m), 7.66
(1H, d, J=1.9 Hz).
C)
4-fluoro-3,3-dimethyl-5-nitro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-i-
ndol-2-one
A suspension of
4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (0.10 g),
2,2,2-trifluoroethyl trifluoromethanesulfonate (0.16 g), potassium
carbonate (0.12 g) and DMF (2 mL) was stirred at room temperature
for 1 hr. To the reaction mixture was added water, and the mixture
was extracted with ethyl acetate. The extract was washed with
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (ethyl acetate/hexane)
to give the title compound (2.2 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.58 (6H, s), 4.37 (2H,
q, J=8.3 Hz), 6.86 (1H, d, J=8.7 Hz), 8.10-8.21 (1H, m).
D)
5-amino-4-fluoro-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-i-
ndol-2-one
By a method similar to Step B of Example 16, and using
4-fluoro-3,3-dimethyl-5-nitro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-ind-
ol-2-one, the title compound was obtained.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.50 (6H, s), 3.58 (2H,
brs), 4.25 (2H, q, J=8.9 Hz), 6.51-6.58 (1H, m), 6.65-6.73 (1H,
m).
E)
4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-
-yl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-indol-2-one
To a mixture of
5-amino-4-fluoro-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-ind-
ol-2-one (300 mg) and 6M hydrochloric acid (1.1 mL) was added
dropwise a solution of sodium nitrite (90 mg) in water (2 mL) at
0.degree. C., and the mixture was stirred for 1 hr. The obtained
aqueous solution was added to a suspension (cooled to 0.degree. C.)
of 1-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-one (250 mg) and
sodium acetate (535 mg) in methanol (5 mL). The reaction mixture
was stirred for 3 hr, and poured into water, and the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
obtained residue was dissolved in acetonitrile (10 mL), and
N,N-dimethylformamide dimethyl acetal (10 mL) was added thereto.
The reaction mixture was stirred overnight at 90.degree. C., and
concentrated under reduced pressure. The residue was purified by
basic silica gel column chromatography (ethyl acetate/hexane), and
recrystallized from ethyl acetate/hexane to give the title compound
(160 mg).
MS (API+), found: 528.2
Example 19
1-(2,2-difluoroethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-
-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
By a method similar to Example 18, and using 2,2-difluoroethyl
trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl
trifluoromethanesulfonate, the title compound was obtained.
MS (API+), found: 510.4
Example 20
4-fluoro-5-[5-methoxy-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-4-oxopyridazin-
-1(4H)-yl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-indol-2-on-
e
A) 1-methoxy-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)propan-2-one
By a method similar to Steps A and B of Example 18, and using
3-methyl-1-phenylpyrazole, the title compound was obtained.
MS (API+), found: 247.4
B)
4-fluoro-5-[5-methoxy-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-4-oxopyrida-
zin-1(4H)-yl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-indol-2-
-one
By a method similar to Step E of Example 18, and using
1-methoxy-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)propan-2-one, the
title compound was obtained.
MS (API+), found: 542.3
Example 21
1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-
-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
A)
1-(cyclopropylmethyl)-4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indo-
l-2-one
To a solution of
4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (300 mg)
in DMF (10 mL) were added sodium hydride (69.6 mg) and
(bromomethyl)cyclopropane (0.193 mL) at 0.degree. C., and the
mixture was allowed to be warmed to room temperature, and stirred
overnight under a nitrogen atmosphere. The reaction mixture was
cooled to 0.degree. C., saturated aqueous ammonium chloride
solution was added thereto, and the mixture was extracted with
ethyl acetate. The extract was washed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(317 mg).
MS (ESI+), found: 279.2
B)
5-amino-1-(cyclopropylmethyl)-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indo-
l-2-one
By a method similar to Step B of Example 16, and using
1-(cyclopropylmethyl)-4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol--
2-one, the title compound was obtained.
MS (ESI+), found: 249.2
C)
1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazo-
l-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
By a method similar to Step E of Example 18, and using
5-amino-1-(cyclopropylmethyl)-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol--
2-one, the title compound was obtained.
MS (ESI+), found: 500.4
Example 22
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-2-ylpyridazin-4(1H)-one
A) (1-phenyl-1H-pyrazol-5-yl)boronic acid
To a solution of 1-phenyl-1H-pyrazole (20.0 g) in THF (700 mL) was
added dropwise n-butyllithium (2.5M hexane solution, 58.3 mL) at
-78.degree. C. under a nitrogen atmosphere, and the mixture was
stirred at the same temperature for 30 min. To the reaction mixture
was added triisopropyl borate (52.2 g) at -78.degree. C., and the
mixture was stirred at the same temperature for 1 hr, gradually
allowed to be warmed to room temperature, and stirred at room
temperature for 20 hr. The pH of the reaction mixture was adjusted
to 5 with acetic acid (20 mL), and concentrated to give the title
compound (25.0 g).
MS (ESI+): [M+H].sup.+ 189.0.
B)
1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(1-Phenyl-1H-pyrazol-5-yl)boronic acid (25.0 g) was dissolved in
toluene (700 mL), pinacol (18.0 g) was added thereto at room
temperature, and the mixture was stirred at 40.degree. C. for 2
days. The reaction mixture was diluted with dichloromethane, and
the mixture was washed with water and saturated brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The resulting
solid was collected by filtration, and washed with hexane to give
the title compound (19.8 g).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27 (12H, s), 6.89 (1H,
d, J=1.6 Hz), 7.33-7.43 (3H, m), 7.52-7.55 (2H, m), 7.72 (1H, d,
J=1.6 Hz).
C) 3-chloro-5-methoxypyridazin-4-ol
3-Chloro-4,5-dimethoxypyridazine (17.0 g) and morpholine (59.0 mL)
were stirred at 100.degree. C. for 2 hr, and cooled to 0.degree. C.
To the reaction mixture was added phenyl isocyanate (73.8 mL) at
0.degree. C., and the mixture was stirred at the same temperature
for 30 min, and diluted with ethyl acetate. The resulting solid was
removed by filtration. The filtrate was concentrated, and the
residue was purified by column chromatography (ethyl
acetate/hexane-methanol/ethyl acetate) to give the title compound
(9.61 g).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.88 (3H, s), 8.26 (1H,
s).
D) 1-benzyl-3-chloro-5-methoxypyridazin-4(1H)-one
3-Chloro-5-methoxypyridazin-4-ol (10.0 g) was dissolved in DMF (300
mL), sodium hydride (3.26 g, 55 wt %) and tetrabutylammonium iodide
(4.60 g) were added thereto at 0.degree. C., and the mixture was
stirred at the same temperature for 10 min. To the reaction mixture
was added benzyl bromide (12.3 g) at 0.degree. C., and the mixture
was stirred at room temperature for 20 hr. The reaction mixture was
diluted with water, and the mixture was extracted with
dichloromethane. The extract was washed with water and saturated
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was recrystallized from ethyl
acetate/hexane to give the title compound (19.8 g).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 3.82 (3H, s), 5.31 (2H,
s), 7.34-7.42 (5H, m), 7.89 (1H, s).
E)
1-benzyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
1-Benzyl-3-chloro-5-methoxypyridazin-4(1H)-one (13.6 g),
1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(22.0 g), potassium carbonate (51.0 g) and
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(1.92 g) were suspended in toluene (330 mL) and water (33.0 mL),
and the suspension was heated under reflux under a nitrogen
atmosphere for 24 hr. The reaction mixture was allowed to be cooled
to room temperature, diluted with water and saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with ethyl acetate. The extract was dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was recrystallized
from ethyl acetate/hexane to give the title compound (15.1 g).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.81 (3H, s), 5.10 (2H,
s), 6.95 (1H, d, J=1.6 Hz), 7.05-7.07 (2H, m), 7.24-7.38 (8H, m),
7.74 (1H, d, J=1.6 Hz), 8.33 (1H, s).
F) 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol
1-benzyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
(15.0 g) and palladium hydroxide on carbon (5.88 g, palladium 20%,
moistened with 50% water) were suspended in THF (500 mL) and
methanol (300 mL), and the suspension was stirred at room
temperature for 2 days under a hydrogen atmosphere. The reaction
mixture was filtered through celite, the filtrate was concentrated.
The residue was solidified with ethanol/hexane to give the title
compound (9.10 g).
MS (ESI+): [M+H].sup.+ 269.2.
G)
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(pyridin-2-yl)pyridazin-4(1H)--
one
A suspension of
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (60 mg),
2-fluoropyridine (65 mg) and cesium carbonate (364 mg) in NMP (2
mL) was stirred at 100.degree. C. for 3 days, 1M hydrochloric acid
was added thereto, and the mixture was extracted with ethyl
acetate. The extract was dried over anhydrous magnesium sulfate,
and the solvent was evaporated under reduced pressure. The residue
was purified by basic silica gel column chromatography (ethyl
acetate/methanol) to give the title compound (20 mg).
MS (API+): [M+H].sup.+ 346.4
Example 23
5-methoxy-1-(1-oxidopyridin-3-yl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(-
1H)-one
To a DMF solution (2.0 ml) of m-chloroperbenzoic acid (0.398 mg)
was added a DMF solution (12.0 ml) of
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(pyridin-3-yl)pyridazin-4(1H)-on-
e at 0.degree. C., and the mixture was stirred overnight at room
temperature. The precipitated solid was collected by filtration to
give the title compound (168 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.87 (3H, s), 6.98 (1H,
d, J=9.82 Hz), 7.15 (1H, d, J=1.89 Hz), 7.27-7.53 (6H, m), 7.82
(1H, d, J=1.89 Hz), 8.18 (1H, d, J=6.42 Hz), 8.38-8.49 (1H, m),
8.58 (1H, s).
Example 24
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(pyrazin-2-yl)pyridazin-4(1H)-one
By a method similar to Example 22, and using 2-fluoropyrazine, the
title compound was obtained.
MS (API+), found: 347.3
Example 25
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-4H-1,3'-bipyridazin-4-one
By a method similar to Example 22, and using 3-chloropyridazine,
the title compound was obtained.
MS (API+), found: 347.0
Example 26
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-pyrimidin-5-ylpyridazin-4(1H)-one
A suspension of
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (100 mg),
5-bromopyrimidine (119 mg), potassium carbonate (155 mg), copper(I)
iodide (14 mg) and 4,7-dimethoxy-1,10-phenanthroline (20 mg) in
DMSO (2 mL) was stirred at 110.degree. C. for 40 hr under an argon
atmosphere. To the reaction mixture was added aqueous sodium
hydrogen carbonate solution, and the mixture was extracted with
ethyl acetate. The extract was dried over anhydrous sodium sulfate,
and the solvent was evaporated under reduced pressure. The residue
was purified by basic silica gel column chromatography (ethyl
acetate/methanol), and recrystallized from ethyl acetate/hexane to
give the title compound (11 mg).
MS (API+), found: 347.3
Example 27
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(1,3-thiazol-2-yl)pyridazin-4(1H)-
-one
By a method similar to Example 22, and using 2-chlorothiazole, the
title compound (44 mg) was obtained.
MS (API+): [M+H].sup.+ 352.3
Example 32
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[6-(3,3,4,4-tetrafluoropyrrolidin-
-1-yl)pyridin-3-yl]pyridazin-4(1H)-one
A) 5-nitro-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridine
Cesium carbonate (100 g) was suspended in DMF (200 ml),
tetrafluoropyrrolidine hydrochloride (10 g) and
2-chloro-5-nitropyridine (20 g) were added thereto, and the mixture
was stirred at room temperature for 90 hr. To the reaction mixture
was added water, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to give the
title compound as yellow crystals.
MS (ESI+): [M+H].sup.+ 266.1
B) 6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-amine
By a method similar to Step B of Example 16, and using
3-nitro-6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridine, the title
compound was obtained.
MS (API+): [M+H].sup.+ 236.2
C)
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[6-(3,3,4,4-tetrafluoropyrroli-
din-1-yl)pyridin-3-yl]pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-amine, the title
compound was obtained.
MS (API+): [M+H].sup.+ 487.1
Example 33
1-[6-(3,4-difluoro-1H-pyrrol-1-yl)pyridin-3-yl]-5-methoxy-3-(1-phenyl-1H-p-
yrazol-5-yl)pyridazin-4(1H)-one
A mixture of
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[6-(3,3,4,4-tetrafluoropyrrolidi-
n-1-yl)pyridin-3-yl]pyridazin-4(1H)-one (367 mg), cesium carbonate
(1.23 g) and DMF (4 ml) was stirred at 100.degree. C. for 4 hr. To
the reaction mixture were added water and ethyl acetate, and the
precipitated crystals were collected by filtration, and
recrystallized from DMSO-ethanol to give the title compound (146
mg) as whitish yellow crystals.
MS (API+): [M+H].sup.+ 447.1
Example 34
1-(1-benzyl-1H-pyrazol-4-yl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridaz-
in-4(1H)-one
To a mixture of 1-benzyl-1H-pyrazol-4-amine (75 mg) and 6M
hydrochloric acid (1 mL) was added dropwise a solution of sodium
nitrite (24 mg) in water (0.5 mL) at 0.degree. C., and the mixture
was stirred for 30 min. The obtained aqueous solution was added to
a suspension (cooled to 0.degree. C.) of
1-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-one (100 mg) and
sodium acetate (354 mg) in methanol (2 mL). The reaction mixture
was stirred for 3 hr, and poured into water, and the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
obtained residue was dissolved in acetonitrile (2 mL), and
N,N-dimethylformamide dimethyl acetal (0.3 mL) was added thereto.
The reaction mixture was stirred at 80.degree. C. for 12 hr, water
was added thereto, and the mixture was extracted with ethyl
acetate. The extract was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (ethyl acetate/methanol) to
give the title compound (11 mg).
MS (API+): [M+H].sup.+ 425.3
Example 35
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[1-(2,2,2-trifluoroethyl)-1H-pyra-
zol-4-yl]pyridazin-4(1H)-one
A) 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine
To a suspension of 4-nitro-1H-pyrazole (500 mg) and potassium
carbonate (1.22 g) in DMF (5 mL) was added dropwise
2,2,2-trifluoroethyl trifluoromethanesulfonate (1.54 g). The
reaction mixture was stirred at room temperature for 4 hr, water
was added thereto, and the mixture was extracted with ethyl
acetate. The extract was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. A suspension of the
obtained residue and palladium on carbon (1 g) in methanol (30 mL)
was stirred at room temperature for 12 hr under a hydrogen
atmosphere, filtered, and concentrated under reduced pressure. The
residue was purified by preparative HPLC to give the title compound
(490 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.97 (2H, brs), 4.88
(2H, q, J=9.1 Hz), 7.04 (1H, s), 7.10 (1H, s)
B)
5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[1-(2,2,2-trifluoroethyl)-1H-p-
yrazol-4-yl]pyridazin-4(1H)-one
By a method similar to Example 34, and using
1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 417.4
Example 36
1-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyrazol-
-5-yl)pyridazin-4(1H)-one
A) 1-(cyclopropylmethyl)-1H-pyrazol-4-amine
By a method similar to Step A of Example 35, and using
(bromomethyl)cyclopropane, the title compound was obtained.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.24-0.33 (2H, m),
0.42-0.54 (2H, m), 1.02-1.20 (1H, m), 3.70-3.88 (4H, m), 6.87 (1H,
s), 7.06 (1H, s).
B)
1-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyra-
zol-5-yl)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(cyclopropylmethyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 389.2
Example 37
1-[1-(dicyclopropylmethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyraz-
ol-5-yl)pyridazin-4(1H)-one
A) 1-(dicyclopropylmethyl)-1H-pyrazol-4-amine
To a solution of 4-nitro-1H-pyrazole (500 mg),
dicyclopropylmethanol (0.92 g) and triphenylphosphine (2.3 g) in
THF (10 mL) was added diisopropyl azodicarboxylate toluene (1.9M,
4.6 mL) solution at room temperature. The reaction mixture was
stirred at room temperature for 2 hr, water was added thereto, and
the mixture was extracted with ethyl acetate. The extract was dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. A suspension of the obtained residue and palladium on
carbon (1 g) in methanol (30 mL) was stirred at room temperature
for 12 hr under a hydrogen atmosphere, filtered, and concentrated
under reduced pressure. The residue was purified by preparative
HPLC to give the title compound (140 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.11-0.24 (2H, m),
0.26-0.42 (4H, m), 0.47-0.63 (2H, m), 1.19-1.37 (2H, m), 2.80 (1H,
t, J=8.7 Hz), 3.73 (2H, s), 6.87 (1H, s), 7.08 (1H, s).
B)
1-[1-(dicyclopropylmethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-py-
razol-5-yl)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(dicyclopropylmethyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 429.1
Example 38
5-methoxy-1-[1-(1-phenylethyl)-1H-pyrazol-4-yl]-3-(1-phenyl-1H-pyrazol-5-y-
l)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(1-phenylethyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 439.4
Example 39
5-methoxy-1-[1-(1-methylethyl)-1H-pyrazol-4-yl]-3-(1-phenyl-1H-pyrazol-5-y-
l)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(1-methylethyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 377.0
Example 40
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyrazo-
l-5-yl)pyridazin-4(1H)-one
A) 1-(1-cyclopropylethyl)-1H-pyrazol-4-amine
By a method similar to Step A of Example 37, and using
1-cyclopropylethanol, the title compound was obtained.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.39-0.50 (2H, m),
0.52-0.63 (1H, m), 0.65-0.76 (1H, m), 1.24-1.37 (1H, m), 1.60 (3H,
d, J=6.8 Hz), 3.56-3.70 (1H, m), 3.97 (2H, brs), 7.08 (1H, s), 7.28
(1H, s).
B)
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyr-
azol-5-yl)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(1-cyclopropylethyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 403.1
Example 41
5-methoxy-3-(1-methyl-1H-pyrazol-5-yl)-1-(pyridin-3-yl)pyridazin-4(1H)-one
An acetonitrile suspension (7.5 mL) of
3-acetyl-5-methoxy-1-(pyridin-3-yl)pyridazin-4(1H)-one (0.5 g) was
stirred at 70.degree. C. for 10 min, and allowed to be cooled to
room temperature. Then, N,N-dimethylformamide dimethyl acetal (2.5
mL) was added thereto, and the mixture was stirred at 80.degree. C.
for 2 hr. The insoluble material was removed by filtration, and the
filtrate was concentrated to dryness under reduced pressure. The
residue was dissolved in ethanol (5.4 mL). To the reaction mixture
was added dropwise a 10%-TFA containing ethanol solution (5.4 mL)
of methylhydrazine (139 mg) under ice-cooling with stirring, and
the mixture was stirred at the same temperature for 10 min, allowed
to be warmed to room temperature, and stirred for 16 hr. The
reaction mixture was concentrated to dryness under reduced
pressure, and the residue was purified by column chromatography
(NH, ethyl acetate/methanol). The eluted product was crystallized
from ethyl acetate to give the title compound (47 mg) as
pale-yellow crystals.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.99 (3H, s), 4.12 (3H,
s), 7.24 (1H, d, J=1.9 Hz), 7.53 (1H, dd, J=8.3, 4.2 Hz), 7.57 (1H,
d, J=1.9 Hz), 7.97-8.04 (2H, m), 8.69-8.73 (1H, m), 8.97 (1H, d,
J=2.6 Hz).
[M+H].sup.+ 284.17.
Example 42
5-methoxy-1-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-3-(1-phenyl-1H-pyrazol-5--
yl)pyridazin-4(1H)-one
A) 1-(2-methylpropyl)-4-nitro-1H-pyrazole
To a DMF solution (30 ml) of 4-nitro-1H-pyrazole (1.00 g) were
added potassium carbonate (3.67 g) and 1-bromo-2-methylpropane
(1.82 g), and the mixture was stirred at 70.degree. C. for 3 hr. To
the reaction mixture was added water, and the mixture was extracted
with ethyl acetate. The extract was washed with saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to give the title compound (4.13 g, containing
DMF).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.95 (6H, d, J=6.8 Hz),
2.17-2.43 (1H, m), 3.95 (2H, d, J=7.2 Hz), 8.09 (2H, d, J=6.4
Hz).
B) 1-(2-methylpropyl)-1H-pyrazol-4-amine
By a method similar to Step B of Example 16, and using
1-(2-methylpropyl)-4-nitro-1H-pyrazole, the title compound was
obtained.
MS (API+): [M+H].sup.+ 140.3
C)
5-methoxy-1-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-3-(1-phenyl-1H-pyrazol-
-5-yl)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(2-methylpropyl)-1H-pyrazol-4-amine, the title compound was
obtained.
MS (API+): [M+H].sup.+ 391.1
Example 43
1-[1-(cyclobutylmethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyrazol--
5-yl)pyridazin-4(1H)-one
By a method similar to Example 42, and using
(bromomethyl)cyclobutane, the title compound (196 mg) was
obtained.
MS (API+): [M+H].sup.+ 403.1
Example 44
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyrazo-
l-5-yl)pyridazin-4(1H)-one (retention time: shorter)
A racemate (140 mg) of
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyraz-
ol-5-yl)pyridazin-4(1H)-one was separated by HPLC (column:
CHIRALCEL OJ (MC001), 50 mmID.times.500 mL, manufactured by DAICEL
CHEMICAL INDUSTRIES, LTD., mobile phase: hexane/ethanol=100/900) to
give the title compound (63 mg) having a shorter retention
time.
MS (API+): [M+H].sup.+ 403.1
Example 45
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyrazo-
l-5-yl)pyridazin-4(1H)-one (retention time: longer)
A racemate (140 mg) of
1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyraz-
ol-5-yl)pyridazin-4(1H)-one was separated by HPLC (column:
CHIRALCEL OJ (MC001), 50 mmID.times.500 mL, manufactured by DAICEL
CHEMICAL INDUSTRIES, LTD., mobile phase: hexane/ethanol=100/900) to
give the title compound (63 mg) having a longer retention time.
MS (API+): [M+H].sup.+ 403.1
Example 46
1-(7-fluoro-1,2-dimethyl-1H-benzimidazol-6-yl)-5-methoxy-3-(1-phenyl-1H-py-
razol-5-yl)pyridazin-4(1H)-one
A) 2,3-difluoro-N-methyl-6-nitroaniline
To a DMF solution (50 mL) of 2,3-difluoro-6-nitroaniline (3.0 g)
were added potassium carbonate (14.3 g), and methyl iodide (3.23
mL), and the mixture was stirred at 50.degree. C. for 4 hr. To the
reaction mixture was added water, and the mixture was extracted
with ethyl acetate. The extract was washed with saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(2.66 g).
MS (ESI+): [M+H].sup.+ 189.1
B)
N.sup.1-(diphenylmethyl)-2-fluoro-N.sup.3-methyl-4-nitrobenzene-1,3-dia-
mine
A mixture of 2,3-difluoro-N-methyl-6-nitroaniline (2.66 g),
1,1-diphenylmethanamine (5.18 g), diisopropylethylamine (4.56 g)
and butan-1-ol (26.6 mL) was heated at 200.degree. C. for 2 hr
using a microwave reactor. To the reaction mixture was added
saturated sodium hydrogen carbonate solution, and the mixture was
extracted with ethyl acetate. The extract was washed with saturated
brine, and dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane) to give the title
compound (1.47 g).
MS (ESI+): [M+H].sup.+ 352.3
C)
N-(diphenylmethyl)-7-fluoro-1,2-dimethyl-1H-benzimidazol-6-amine
To a mixture of
N.sup.1-(diphenylmethyl)-2-fluoro-N.sup.3-methyl-4-nitrobenzene-1,3-diami-
ne (1.47 g), zinc (1.37 g), methanol (21 mL) and THF (21 mL) was
added dropwise saturated aqueous ammonium chloride solution (17
mL), and the mixture was stirred at room temperature for 3 hr. To
the reaction mixture was added saturated ammonium acetate solution,
and the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. To the residue
were added ethanol (42 mL), triethylamine (1.17 mL) and acetamidine
hydrochloride (0.79 g), and the mixture was stirred at 100.degree.
C. for 6 hr, and concentrated under reduced pressure. The residue
is was purified by silica gel column chromatography (ethyl
acetate/hexane) to give the title compound (0.58 g).
MS (ESI+): [M+H].sup.+ 364.4
D) 7-fluoro-1,2-dimethyl-1H-benzimidazol-6-amine
To a THF solution (10 mL) of
N-(diphenylmethyl)-7-fluoro-1,2-dimethyl-1H-benzimidazol-6-amine
was added 6N hydrochloric acid (10 mL), and the mixture was stirred
at 100.degree. C. for 2 hr, cooled, and concentrated under reduced
pressure. The precipitated crystals were washed with methanol to
give the title compound dihydrochloride (244 mg).
The washing was charged into MP-TsOH column, the column was washed
with methanol, and was eluted with 0.5 M ammonia/methanol solution
to give the title compound (100 mg).
MS (ESI+): [M+H].sup.+ 180.2
E)
1-(7-fluoro-1,2-dimethyl-1H-benzimidazol-6-yl)-5-methoxy-3-(1-phenyl-1H-
-pyrazol-5-yl)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
7-fluoro-1,2-dimethyl-1H-benzimidazol-6-amine, the title compound
was obtained.
MS (API+): [M+H].sup.+ 431.3
Example 47
4'-fluoro-5'-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)--
yl]-1'-methylspiro[cyclobutane-1,3'-indol]-2' (1'H)-one
A) methyl 1-(2-fluoro-6-nitrophenyl)cyclobutanecarboxylate
To a solution of sodium hydride (9.49 g) in DMF (75 mL) was added
dropwise a solution of methyl (2-fluoro-6-nitrophenyl)acetate (23
g) and 1,3-dibromopropane (13.1 mL) in DMF (15 mL) at 0.degree. C.
The reaction mixture was stirred at room temperature for 4 hr,
cooled to 0.degree. C. Saturated aqueous ammonium chloride solution
was added thereto, and the mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(11.3 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.75-1.91 (1H, m),
2.37-2.54 (3H, m), 2.71-2.86 (2H, m), 3.77 (3H, s), 7.28-7.41 (2H,
m), 7.52-7.58 (1H, m).
B) 4'-fluorospiro[cyclobutane-1,3'-indol]-2' (1'H)-one
To a solution of methyl
1-(2-fluoro-6-nitrophenyl)cyclobutanecarboxylate (3.11 g) in acetic
acid (60 mL) was added zinc (16.1 g), and the mixture was stirred
overnight at room temperature. The zinc was removed by filtration,
and the filtrate was concentrated under reduced pressure, and the
residue was dissolved in ethyl acetate. The solution was washed
with saturated aqueous sodium hydrogen carbonate solution, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(2.30 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.24-2.45 (2H, m),
2.56-2.71 (4H, m), 6.62-6.82 (2H, m), 7.16 (1H, td, J=8.1, 5.3 Hz),
8.44 (1H, brs).
C) 4'-fluoro-5'-nitrospiro[cyclobutane-1,3'-indol]-2' (1'H)-one
By a method similar to Step A of Example 16, and using
4'-fluorospiro[cyclobutane-1,3'-indol]-2'(1'H)-one, the title
compound was obtained.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.14-2.35 (2H, m),
2.36-2.67 (4H, m), 6.83 (1H, d, J=8.7 Hz), 8.11 (1H, dd, J=8.7, 7.9
Hz), 11.13 (1H, brs).
D) 4'-fluoro-1'-methyl-5'-nitrospiro[cyclobutane-1,3'-indol]-2'
(1'H)-one
To a solution of 4'-fluoro-5'-nitrospiro[cyclobutane-1,3'-indol]-2'
(1'H)-one (300 mg) and sodium hydride (36.6 mg) in DMF (10 mL) was
added methyl iodide (0.395 mL) at 0.degree. C., and the mixture was
stirred at room temperature for 1 hr under a nitrogen atmosphere.
To the reaction mixture was added saturated aqueous ammonium
chloride solution at 0.degree. C., and the mixture was extracted
with ethyl acetate. The extract was washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane) to give the title
compound (282 mg).
MS (ESI+), found: 251.1
E) 5'-amino-4'-fluoro-1'-methylspiro[cyclobutane-1,3'-indol]-2'
(1'H)-one
By a method similar to Step B of Example 16, and using
4'-fluoro-1'-methyl-5'-nitrospiro[cyclobutane-1,3'-indol]-2'
(1'H)-one, the title compound was obtained.
MS (API+), found: 221.2
F)
4'-fluoro-5'-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4-
H)-yl]-1'-methylspiro[cyclobutane-1,3'-indol]-2' (1'H)-one
By a method similar to Step E of Example 18, and using
5'-amino-4'-fluoro-1'-methylspiro[cyclobutane-1,3'-indol]-2'(1'H)-one,
the title compound was obtained.
MS (ESI+), found: 472.3
Example 48
4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl-
]-3,3-dimethyl-1-(1-methylethyl)-1,3-dihydro-2H-indol-2-one
A)
5-amino-4-fluoro-3,3-dimethyl-1-(1-methylethyl)-1,3-dihydro-2H-indol-2--
one
To a solution of
4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (500 mg)
and cesium carbonate (1.82 g) in DMF (10 mL) was added dropwise
2-bromopropane (0.523 mL) at room temperature, and the mixture was
stirred at 80.degree. C. for 2 hr under a nitrogen atmosphere. To
the reaction mixture was added saturated aqueous ammonium chloride
solution at 0.degree. C., and the mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was dissolved in ethanol (10
mL), palladium on carbon (containing water (50%), 237 mg) was added
thereto, and the mixture was stirred at room temperature for 2 hr
under a hydrogen atmosphere. The palladium on carbon was removed by
filtration, and the filtrate was concentrated under reduced
pressure to give the title compound (330 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.40-1.48 (12H, m), 3.54
(2H, brs), 4.58 (1H, quin, J=7.0 Hz), 6.55-6.70 (2H, m).
B)
4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-
-yl]-3,3-dimethyl-1-(1-methylethyl)-1,3-dihydro-2H-indol-2-one
By a method similar to Step E of Example 18, and using
5-amino-4-fluoro-3,3-dimethyl-1-(1-methylethyl)-1,3-dihydro-2H-indol-2-on-
e, the title compound was obtained.
MS (ESI+), found: 488.4
Example 49
4'-fluoro-5'-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)--
yl]-1'-(1-methylethyl)spiro[cyclobutane-1,3'-indol]-2'
(1'H)-one
A)
5'-amino-4'-fluoro-1'-(1-methylethyl)spiro[cyclobutane-1,3'-indol]-2'
(1'H)-one
By a method similar to Step A of Example 48, and using
2-bromopropane, the title compound was obtained.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.40 (3H, s), 1.43 (3H,
s), 2.27-2.40 (2H, m), 2.53-2.63 (4H, m), 3.55 (2H, brs), 4.57 (1H,
quin, J=7.1 Hz), 6.52-6.58 (1H, m), 6.60-6.69 (1H, m).
B)
4'-fluoro-5'-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4-
H)-yl]-1'-(1-methylethyl)spiro[cyclobutane-1,3'-indol]-2'
(1'H)-one
By a method similar to Step E of Example 18, and using
5'-amino-4'-fluoro-1'-(1-methylethyl)spiro[cyclobutane-1,3'-indol]-2'(1'H-
)-one, the title compound was obtained.
MS (ESI+), found: 500.4
Example 50
1-cyclobutyl-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyrid-
azin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
A)
1-cyclobutyl-4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one
To a solution of
4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (300 mg),
cyclobutanol (0.136 mL) and triphenylphosphine (702 mg) in THF (15
mL) was added dropwise diethyl azocarboxylate (40% toluene
solution, 1.48 mL) at 0.degree. C., and the mixture was stirred for
5 hr under a nitrogen atmosphere. To the reaction mixture was added
water at 0.degree. C., and the mixture was extracted with ethyl
acetate. The extract was washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane) to give the title compound
(200 mg).
MS (ESI+), found: 279.2
B)
5-amino-1-cyclobutyl-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
By a method similar to Step B of Example 16, and using
1-cyclobutyl-4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one,
the title compound was obtained.
MS (ESI+), found: 249.1
C)
1-cyclobutyl-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)py-
ridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
By a method similar to Step E of Example 18, and using
5-amino-1-cyclobutyl-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one,
the title compound was obtained.
MS (ESI+), found: 500.4
Example 51
1-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(3-methyl-1-phenyl-1-
H-pyrazol-5-yl)pyridazin-4(1H)-one
By a method similar to Step E of Example 18, and using
1-(cyclopropylmethyl)-1H-pyrazol-4-amine and
1-methoxy-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)propan-2-one, the
title compound was obtained.
MS (API+), found: 403.4
Example 52
5-methoxy-1-[2-methoxy-6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-yl]-
-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
By a method similar to Example 32, and using
2-chloro-6-methoxy-5-nitropyridine, the title compound was
obtained.
MS (API+), found: 517.2
Example 53
1-[6-(3,4-difluoro-1H-pyrrol-1-yl)-2-methoxypyridin-3-yl]-5-methoxy-3-(1-p-
henyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
By a method similar to Example 32, and using
5-methoxy-1-[2-methoxy-6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-yl-
]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, the title
compound was obtained.
MS (API+), found: 477.1
Example 54
5-methoxy-1-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}-3-(1-phenyl--
1H-pyrazol-5-yl)pyridazin-4(1H)-one
By a method similar to Step A of Example 35 and Step E of Example
18, and using 1-(bromomethyl)-1-methylcyclopropane, the title
compound was obtained.
MS (API+), found: 403.1
Example 55
5-methoxy-1-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-3-(1-phenyl--
1H-pyrazol-5-yl)pyridazin-4(1H)-one
By a method similar to Step A of Example 35 and Step E of Example
18, and using 2,2,3,3,3-pentafluoropropyl
trifluoromethanesulfonate, the title compound was obtained.
MS (API+), found: 467.3
The structures and the like of the compound of Examples 1 to 55 are
shown in Tables 1 to 11. The structures and the like of the
compound of Examples 56 to 102, which were synthesized according to
the synthetic method of Examples 1 to 55, are shown in Tables 11 to
20.
TABLE-US-00001 TABLE 1 Ex. No. IUPAC NAME Structure MS 1
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-(3-
methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00042##
443.3 2 5-methoxy-1-[2-methoxy-4-(1H- pyrazol-1-yl)phenyl]-3-(3-
methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00043##
455.3 3 3-[1-(3-chloro-2-fluorophenyl)-
1H-pyrazol-5-yl]-1-[2-fluoro-4- (1H-pyrazol-1-yl)phenyl]-5-
methoxypyridazin-4(1H)-one ##STR00044## 481.3 4
3-[1-(5-chloro-2-fluorophenyl)- 1H-pyrazol-5-yl]-1-[2-f1uoro-4-
(1H-pyrazol-1-yl)phenyl]-5- methoxypyridazin-4(1H)-one ##STR00045##
481.3 5 1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-{1-[3-
(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)- one
##STR00046## 497.2
TABLE-US-00002 TABLE 2 Ex. No. IUPAC NAME Structure MS 6
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-[1-
(2,2,2-trifluoroethyl)-1H- pyrazol-5-yl]pyridazin-4(1H)- one
##STR00047## .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.86 (3H,
s), 5.36 (2H, q, J = 8.9 Hz), 6.65 (1H, d, J = 2.6 Hz), 7.17 (1H,
d, J = 1.9 Hz), 7.86 (1H, d, J = 1.5 Hz), 7.89-7.99 (2H, m), 8.08
(1H, d, J = 1.9 Hz), 8.64 (1H, s), 8.70 (1H, d, J = 2. 6 Hz). 7
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-{1-[3-
(trifluoromethoxy)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)- one
##STR00048## .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3. 79 (3H,
s), 6.64 (1H, d, J = 2.6 Hz), 7.03 (1H, d, J = 1.9 Hz), 7.27-7.49
(4H, m), 7.57 (1H, t, J = 8.1 Hz), 7.74-7.88 (3H, m), 7.99 (1H, dd,
J = 12.1, 2.3 Hz), 8.57 (1H, d, J = 1.9 Hz), 8.66 (1H, d, J = 2.6
Hz). 8 5-methoxy-1-[2-methoxy-4-(1H- pyrazol-1-yl)phenyl]-3-{1-[3-
(trifluoromethyl)phenyl]-1H- pyrazol-5-yl}pyridazin-4(1H)- one
##STR00049## 509.5 9 3-[1-(3-chlorophenyl)-1H-
pyrazol-5-y1]-5-methoxy-1-[2- methoxy-4-(1H-pyrazol-1-
yl)phenyl]pyridazin-4(1H)-one ##STR00050## 475.5 10
1-[2-(benzyloxy)-4-(3,4- difluoro-1H-pyrrol-1-
yl)phenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00051## 552.6
TABLE-US-00003 TABLE 3 Ex. No. IUPAC NAME Structure MS 11
1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-hydroxyphenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00052## 462.4
12 1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-methoxyphenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00053## 476.4
13 1-[2-(difluoromethoxy)-4-(3,4- difluoro-1H-pyrrol-1-
yl)phenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00054## 512.5 14
1-[4-(3,4-difluoro-1H-pyrrol-1- yl)-2-(2,2,2-
trifluoroethoxy)phenyl]-5- methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)pyridazin-4(1H)-one ##STR00055## 544.5 15
5-methoxy-1-[2-methoxy-4- (3,3,4,4-tetrafluoropyrrolidin-
1-yl)phenyl]-3-(1-phenyl-1H- pyrazol-5-yl)pyridazin-4(1H)- one
##STR00056## 516.5 16 4-fluoro-5-[5-methoxy-4-oxo-3-
(1-phenyl-1H-pyrazol-5- yl)pyridazin-1(4H)-yl]-1,3,3-
trimethyl-1,3-dihydro-2H-indol- 2-one ##STR00057## 460.3
TABLE-US-00004 TABLE 4 Ex. No. IUPAC NAME Structure MS 17
5-{3-[1-(3-chlorophenyl)-1H- pyrazol-5-yl]-5-methoxy-4-
oxopyridazin-1(4H)-yl}-4- fluoro-1,3,3-trimethyl-1,3-
dihydro-2H-indol-2-one ##STR00058## 494.2 18
4-fluoro-5-[5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-
yl)pyridazin-1(4H)-yl]-3,3- dimethyl-1-(2,2,2-
trifluoroethyl)-1,3-dihydro-2H- indol-2-one ##STR00059## 528.2 19
1-(2,2-difluoroethyl)-4-fluoro- 5-[5-methoxy-4-oxo-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin- 1(4H)-yl]-3,3-dimethyl-1,3-
dihydro-2H-indol-2-one ##STR00060## 510.4 20
4-fluoro-5-[5-methoxy-3-(3- methyl-1-phenyl-1H-pyrazol-5-
yl)-4-oxopyridazin-1(4H)-yl]- 3,3-dimethyl-1-(2,2,2-
trifluoroethyl)-1,3-dihydro-2H- indol-2-one ##STR00061## 542.3
TABLE-US-00005 TABLE 5 Ex. No. IUPAC NAME Structure MS 21
1-(cyclopropylmethyl)-4-fluoro-5-[5- methoxy-4-oxo-3-(1-phenyl-1H-
pyrazol-5-yl)pyridazin-1(4H)- yl]-3,3-dimethyl-1,3-dihydro-
2H-indol-2-one ##STR00062## 500.4 22
5-methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)-1-pyridin-2-ylpyridazin-4(1H)- one ##STR00063## 346.4 23
5-methoxy-1-(1-oxidopyridin-3-yl)- 3-(1-phenyl-1H-pyrazol-5-yl)
pyridazin-4(1H)-one ##STR00064## 362.0 24
5-methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)-1-pyrazin-2-ylpyridazin-4(1H)- one ##STR00065## 347.0 25
5-methoxy-3-(1-phenyl-1H-pyrazol- 5-yl)-4H-1,3'-bipyridazin-4-one
##STR00066## 347.0
TABLE-US-00006 TABLE 6 Ex. No. IUPAC NAME Structure MS 26
5-methoxy-3-(1-phenyl-1H- pyrazol-5-yl)-1-pyrimidin-5-
ylpyridazin-4(1H)-one ##STR00067## 347.3 27
5-methoxy-3-(1-phenyl-1H- pyrazol-5-yl)-1-(1,3-thiazol-2-
yl)pyridazin-4(1H)-one ##STR00068## 352.3 32
5-methoxy-3-(1-phenyl-1H- pyrazol-5-yl)-1-[6-(3,3,4,4-
tetrafluoropyrrolidin-1- yl)pyridin-3-yl]pyridazin- 4(1H)-one
##STR00069## 487.1 33 1-[6-(3,4-difluoro-1H-pyrrol-1-
yl)pyridin-3-yl]-5-methoxy-3- (1-phenyl-1H-pyrazol-5-
yl)pyrdizan-4(1H)-one ##STR00070## 447.1 34
1-(1-benzyl-1H-pyrazol-4-yl)-5- methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)pyridazin-4(1H)-one ##STR00071## 425.3
TABLE-US-00007 TABLE 7 Ex. No. IUPAC NAME Structure MS 35
5-methoxy-3-(1-phenyl-1H- pyrazol-5-yl)-1-[1-(2,2,2-
trifluoroethyl)-1H-pyrazol-4- yl]pyridazin-4(1H)-one ##STR00072##
417.4 36 1-[1-(cyclopropylmethyl)-1H- pyrazol-4-yl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00073## 389.2 37
1-[1-(dicyclopropylmethyl)-1H- pyrazol-4-yl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00074## 429.1 38
5-methoxy-1-[1-(1-phenylethyl)- 1H-pyrazol-4-yl]-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin- 4(1H)-one ##STR00075## 439.4 39
5-methoxy-1-[1-(1-methylethyl)- 1H-pyrazol-4-yl]-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin- 4(1H)-one ##STR00076## 377.0
TABLE-US-00008 TABLE 8 Ex. No. IUPAC NAME Structure MS 40
1-[1-(1-cyclopropylmethyl)-1H- pyrazol-4-yl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00077## 403.1 41
5-methoxy-3-(1-methyl-1H- pyrazol-5-yl)-1-pyridin-3-
ylpyridazin-4(1H)-one ##STR00078## 284.2 42 5-methoxy-1-[1-(2-
methylpropyl)-1H-pyrazol-4-yl]- 3-(1-phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00079## 391.1 43
1-[1-(cyclobutylmethyl)-1H- pyrazol-4-yl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00080## 403.1 44
1-[1-(1-cyclopropylmethyl)-1H- pyrazol-4-yl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00081## 403.1
TABLE-US-00009 TABLE 9 Ex. No. IUPAC NAME Structure MS 45
1-[1-(1-cyclopropylethyl)-1H- pyrazol-4-yl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00082## 403.1 46
1-(7-fluoro-1,2-dimethyl-1H- benzimidazol-6-yl)-5-methoxy-3-
(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00083## 431.3
47 4'-fluoro-5'-[5-methoxy-4-oxo- 3-(1-phenyl-1H-pyrazol-5-
yl)pyridazin-1(4H)-yl]-1'- methylspiro[cyclobutane-1,3'-
indol]-2'(1'H)-one ##STR00084## 472.3 48
4-fluoro-5-[5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-
yl)pyridazin-1(4H)-yl]-3,3- dimethyl-1-(1-methylethyl)-1,3-
dihydro-2H-indol-2-one ##STR00085## 488.4 49
4'-fluoro-5'-[5-methoxy-4-oxo- 3-(1-phenyl-1H-pyrazol-5-
yl)pyridazin-1(4H)-yl]-1'-(1- methylethyl)spiro[cyclobutane-
1,3'-indol]-2'(1'H)-one ##STR00086## 500.4
TABLE-US-00010 TABLE 10 Ex. No. IUPAC NAME Structure MS 50
1-cyclobutyl-4-fluoro-5-[5- methoxy-4-oxo-3-(1-phenyl-1H-
pyrazol-5-yl)pyridazin-1(4H)- yl]-3,3-dimethyl-1,3-dihydro-
2H-indol-2-one ##STR00087## 500.4 51 1-[1-(cyclopropylmethyl)-1H-
pyrazol-4-yl]-5-methoxy-3-(3- methyl-1-phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00088## 403.4 52
5-methoxy-1-[2-methoxy-6- (3,3,4,4-tetrafluoropyrrolidin-
1-yl)pyridin-3-yl]-3-(1-phenyl- 1H-pyrazol-5-yl)pyridazin-
4(1H)-one ##STR00089## 517.2 53 1-[6-(3,4-difluoro-1H-pyrrol-1-
yl)-2-methoxypyridin-3-yl]-5- methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)pyridazin-4(1H)-one ##STR00090## 477.1 54 5-methoxy-1-{1-[(1-
methylcyclopropyl)methyl]-1H- pyrazol-4-yl}-3-(1-phenyl-1H-
pyrazol-5-yl)pyridazin-4(1H)- one ##STR00091## 403.1
TABLE-US-00011 TABLE 11 Ex. No. IUPAC NAME Structure MS 55
5-methoxy-1-[1-(2,2,3,3,3- pentafluoropropyl)-1H-pyrazol-
4-yl]-3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00092##
467.3 56 5-amino-3-(1-phenyl-1H-pyrazol- 5-yl)-1-[3-
(trifluoromethyl)phenyl]pyridazin- 4(1H)-one ##STR00093## 398.4 57
5-(methylamino)-3-(1-phenyl-1H- pyrazol-5-yl)-1-[3-
(trifluoromethyl)phenyl]pyridazin- 4(1H)-one ##STR00094## 412.4 58
5-(dimethylamino)-3-(1-phenyl- 1H-pyrazol-5-yl)-1-[3-
(trifluoromethyl)phenyl]pyridazin- 4(1H)-one ##STR00095## 426.4 59
1-[2-(difluoromethoxy)-4- (3,3,4,4-tetrahydrofluoropyrrolidin-
1-yl)phenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00096## 552.2
TABLE-US-00012 TABLE 12 Ex. No. IUPAC NAME Structure MS 60
1-[2-fluoro-4-(5-methoxy-1H- pyrazol-1-yl)phenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00097## 459.2
61 1-{4-[5-(cyclopropylmethoxy)- 1H-pyrazol-1-yl]-2-
fluorophenyl}-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00098## 499.3 62
1-{2-fluoro-4-[5-(2,2,2- trifluoroethoxy)-1H-pyrazol-1-
yl]phenyl}-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00099## 527.3 63
1-[4-(3,3-difluoropiperidin-1- yl)-2-fluorophenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00100## 482.2
64 1-[2-fluoro-4-(3-methyl-2- oxopyrrolidin-1-yl)phenyl]-5-
methoxy-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one
##STR00101## 460.3
TABLE-US-00013 TABLE 13 Ex. No. IUPAC NAME Structure MS 65
1-[2-fluoro-4-(2-oxopyrrolidin- 1-yl)phenyl]-5-methoxy-3-(3-
methyl-1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00102##
460.3 66 3-[1-(3-chlorophenyl)-1H- pyrazol-5-yl]-1-(2-fluoro-4-
iodophenyl)-5-methoxypyridazin- 4(1H)-one ##STR00103## 523.1 67
3-[1-(3-chlorophenyl)-1H- pyrazol-5-yl]-1-[2-fluoro-4-(2-
oxopyrrolidin-1-yl)phenyl]-5- methoxypyridazin-4(1H)-one
##STR00104## 480.2 68 1-(2-fluoro-4-iodophenyl)-3-[1-
(2-fluorophenyl)-1H-pyrazol-5- yl]-5-methoxypyridazin-4(1H)- one
##STR00105## 506.9 69 1-[2-fluoro-4-(2-oxopyrrolidin-
1-yl)phenyl]-3-[1-(2- fluorophenyl)-1H-pyrazol-5-yl]-
5-methoxypyridazin-4(1H)-one ##STR00106## 464.3
TABLE-US-00014 TABLE 14 Ex. No. IUPAC NAME Structure MS 70
1-[2-(difluoromethoxy)-4- iodophenyl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00107## 537.2 71
1-[2-(difluoromethoxy)-4-(1H- pyrazol-1-yl)phenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00108## 477.3
72 1-[2-(difluoromethoxy)-4-(2- oxopyrrolidin-1-yl)phenyl]-5-
methoxy-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one
##STR00109## 494.4 73 1-[2-fluoro-4-(2-methyl-5-
oxopyrrolidin-1-yl)phenyl]-5- methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)pyridazin-4(1H)-one ##STR00110## 460.4 74
5-methoxy-3-(1-phenyl-1H- pyrazol-5-yl)-1-[4-(1H-pyrazol-
1-yl)-2-(2,2,2- trifluoroethoxy)phenyl]pyridazin- 4(1H)-one
##STR00111## 509.3
TABLE-US-00015 TABLE 15 Ex. No. IUPAC NAME Structure MS 75
1-[2-(2,2-difluoroethoxy)-4- (1H-pyrazol-1-yl)phenyl]-5-
methoxy-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one
##STR00112## 491.3 76 1-[2-fluoro-4-(3-methyl-2-
oxopyrrolidin-1-yl)phenyl]-5- methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)pyridazin-4(1H)-one ##STR00113## 460.2 77
1-[2-fluoro-4-(3-methyl-2- oxopyrrolidin-1-yl)phenyl]-5-
methoxy-3-(1-phenyl-1H-pyrazol- 5-yl)pyridazin-4(1H)-one
##STR00114## 460.2 78 3-(1-cyclohexyl-1H-pyrazol-5-
yl)-1-[2-fluoro-4-(1H-pyrazol- 1-yl)phenyl]-5-
methoxypyridazin-4(1H)-one ##STR00115## .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.19 (3H, d, J = 8.7 Hz), 1.76 (4H, d, J =
15.8 Hz), 1.86 (3H, brs), 3.84 (3H, s), 4.50 (1H, t, J = 5.1 Hz),
6.64 (1H, d, J = 1.9 Hz), 6.83 (1H, d, J = 1.9 Hz), 7.52 (1H, d, J
= 1.9 Hz), 7.85 (1H, d, J = 1.9 Hz), 7.96 (2H, d, J = 4.5 Hz), 8.09
(1H, d, J = 11.7 Hz), 8.61 (1H, d, J = 1.5 Hz), 8.70 (1H, d, J =
2.3 Hz). 79 1-(4-iodophenyl)-5-methoxy-3- (1-phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00116## 471.2
TABLE-US-00016 TABLE 16 Ex. No. IUPAC NAME Structure MS 80
1-{4-[(2R,6S)-2,6- dimethylmorpholin-4-yl]-2-
fluorophenyl}-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00117## 476.3 81
1-(4-iodo-2-methoxyphenyl)-5- methoxy-3-(1-phenyl-1H-pyrazol-
5-yl)pyridazin-4(1H)-one ##STR00118## 501.1 82
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-(1H-
pyrazol-5-yl)pyridazin-4(1H)-one ##STR00119## 353.3 83
1-[2-fluoro-4-(8-oxa-3- azabicyclo[3.2.1]oct-3-
yl)phenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00120## 474.5 84
1-[2-fluoro-4-(1,4-oxazepan-4- yl)phenyl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00121## 462.4
TABLE-US-00017 TABLE 17 Ex. No. IUPAC NAME Structure MS 85
5-methoxy-6-methyl-3-(1-phenyl- 1H-pyrazol-5-yl)-1-[4-(1H-
pyrazol-1-yl)phenyl]pyridazin- 4(1H)-one ##STR00122## 425.3 86
5-methoxy-6-methyl-1-[4-(2- oxopyrrolidin-1-yl)phenyl]-3-
(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00123## 442.3
87 1-[2-fluoro-4-(1H-pyazol-1- yl)phenyl]-5-methoxy-3-(1-
methyl-1H-pyrazol-3- yl)pyridazin-4(1H)-one ##STR00124## 367.1 88
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-(1-
methyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00125## 367.0 89
1-[4-(3,3-dimethyl-2- oxopyrrolidin-1-yl)-2-
fluorophenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00126## 474.4
TABLE-US-00018 TABLE 18 Ex. No. IUPAC NAME Structure MS 90
1-[4-(3,3-dimethyl-2- oxopyrrolidin-1-yl)-2-
methoxyphenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00127## 486.4 91
5-methoxy-3-(1-phenyl-1H- pyrazol-5-yl)-1-[4-(1H-pyrazol-
1-yl)phenyl]pyridazin-4(1H)-one ##STR00128## 411.4 92
1-[2-(difluoromethoxy)-4-(3,3- dimethyl-2-oxopyrrolidin-1-
yl)phenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00129## 522.5 93
1-(2-fluoro-4-iodophenyl)-5- methoxy-3-(2-phenyl-1H-
imidazol-1-yl)pyridazin-4(1H)- one ##STR00130## 488.9 94
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-(2-
phenyl-1H-imidazol-1- yl)pyridazin-4(1H)-one ##STR00131## 429.1
TABLE-US-00019 TABLE 19 Ex. No. IUPAC NAME Structure MS 95
1-[2-fluoro-3-(1H-pyrazol-1- yl)phenyl]-5-methoxy-3-(1-
phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00132## 429.1 96
1-[2-(2,2-difluoroethoxy)-4- (3,4-difluoro-1H-pyrrol-1-
yl)phenyl]-5-methoxy-3-(1- phenyl-1H-pyrazol-5-
yl)pyridazin-4(1H)-one ##STR00133## 526.5 97
3-[1-(4-fluorophenyl)-1H- pyrazol-5-yl]-1-[2-fluoro-4-
(1H-pyrazol-1-yl)phenyl]-5- methoxypyridazin-4(1H)-one ##STR00134##
447.4 98 3-{1-[3-(benzyloxy)phenyl]-1H-
pyrazol-5-yl}-1-[2-fluoro-4- (1H-pyrazol-1-yl)phenyl]-5-
methoxypyridazin-4(1H)-one ##STR00135## 535.3
TABLE-US-00020 TABLE 20 Ex. No. IUPAC NAME Structure MS 99
1-[2-fluoro-4-(1H-pyrazol-1- yl)phenyl]-3-[1-(3-
hydroxyphenyl)-1H-pyrazol-5- yl]-5-methoxypyridazin-4(1H)- one
##STR00136## 445.1 100 3-{1-[3- (cyclopropylmethoxy)phenyl]-1H-
pyrazol-5-yl}-1-[2-fluoro-4- (1H-pyrazol-1-yl)phenyl]-5-
methoxypyridazin-4(1H)-one ##STR00137## 499.4 101
1-[2-fluoro-4-(4-hydroxy-1H- pyrazol-1-yl)phenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00138## 445.1
102 1-[2-fluoro-4-(3-hydroxy-1H- pyrazol-1-yl)phenyl]-5-methoxy-
3-(1-phenyl-1H-pyrazol-5- yl)pyridazin-4(1H)-one ##STR00139##
445.1
Formulation Example 1
TABLE-US-00021 (1) Compound of the Example 16 10.0 g (2) Lactose
70.0 g (3) Cornstarch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium
stearate 3.0 g
The compound of Example 16 (10.0 g) and magnesium stearate (3.0 g)
are granulated with an aqueous solution (70 ml) of soluble starch
(7.0 g as soluble starch), dried, and the resulting mixture is
mixed with lactose (70.0 g) and cornstarch (50.0 g) (lactose,
cornstarch, soluble starch and magnesium stearate are all products
on the Japanese Pharmacopoeia). The mixture is compressed to give
tablets.
Experimental Example 1
PDE10A Enzyme Activity Inhibition Test
Human PDE10A full-length gene was transfected into Sf9 or COS-7
cells, the cells were disrupted and centrifuged, and human PDE10A
enzyme was obtained from the residue. The enzyme extracted from Sf9
cells was partially purified using His-tag affinity column. The
enzyme was stored at -70.degree. C. until use. The PDE activity was
measured using an SPA (Scintillation Proximity Assay) (GE
Healthcare). To measure the inhibitory activity of the compound, 10
.mu.L of serially diluted compound was reacted with 20 .mu.L of PDE
enzyme in an assay buffer (50 mM HEPES-NaOH, 8.3 mM MgCl.sub.2, 1.7
mM EGTA, 0.1% BSA (pH 7.4)) for min at room temperature. The final
concentration of DMSO in the reaction mixture was 1 percent. The
compounds were evaluated in duplicate in 96-well half-area plates
(Corning). To start the reaction, 10 .mu.L of substrate [.sup.3H]
cGMP (25 and 50 nM; GE Healthcare and PerkinElmer, respectively)
was added to 40 .mu.L. After 60 min of reaction at room
temperature, yttrium SPA beads containing zinc sulphate were added
(6 mg/mL, 20 .mu.L) to terminate the PDE reaction. After standing
still for 1 hr, the measurement was performed using a scintillation
counter (PerkinElmer) and the PDE10A enzyme activity inhibition
rate was calculated. The inhibition rate was calculated based on
the control containing enzyme and DMSO as 0% and the control
without enzyme as 100%. The results are shown in Tables 21 and
22.
TABLE-US-00022 TABLE 21 IC.sub.50 A: 10 nM .gtoreq. Inhibition rate
(%) Example No. B: 10~200 nM (100 nM) 12 A 100 15 A 99 16 A 100 17
A 99 18 A 100 19 A 102 20 A 100 21 A 100 22 A 100 24 A 97 25 B 88
26 B 85 27 A 98 32 A 100 33 A 96
TABLE-US-00023 TABLE 22 IC.sub.50 A: 10 nM .gtoreq. Inhibition rate
(%) Example No. B: 10~200 nM (100 nM) 35 A 100 36 A 102 42 A 100 43
A 99 44 A 102 45 A 100 46 A 98 47 A 101 48 A 101 49 A 101 50 A 101
51 A 102 52 A 101 53 A 97 54 A 101
Experimental Example 2
Animals
Male ICR mice were supplied by CLEA Japan, Inc (Japan). After
arrival to the vivarium, animals were allowed a minimum of 1 week
for acclimation and used for the test. They were housed under a
12:12-h light/dark cycle in a temperature- and humidity-controlled
laboratory and allowed food and water ad libitum. The care and use
of the animals and the experimental protocols used in this research
were approved by the Experimental Animal Care and Use Committee of
Takeda Pharmaceutical Company, Ltd (Osaka, Japan).
Drug Administration
The test compound was suspended in 0.5% methylcellulose in
distilled water, and orally administered (p.o.). MK-801 hydrogen
maleate
((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin-
e hydrogen maleate (Sigma-Aldrich, St Louis, Mo.) was dissolved in
saline, and administered subcutaneously (s.c.). All drugs were
dosed in a volume of 20 mL/kg body weight for mice.
Inhibition of MK-801-Induced Locomotor Hyperactivity
The evaluation of the extent of hyperlocomotion induced by
psychostimulants (e.g., amphetamine, cocaine, methamphetamine,
MK-801 and phencyclidine) in rodents has been widely used as animal
models of psychotic diseases (Schizophrenia Bulletin 2010, vol. 36:
1066-1072; Psychopharmacology 1999, vol. 145: 237-250). The
compounds were tested for their ability to suppress MK-801-induced
hyperlocomotion in mice. Male ICR mice (30-43 g) were acclimated in
locomotor chambers with infrared sensors (BrainScienceIdea Co.,
Ltd. Japan) for at least 60 minutes. After the acclimation, animals
were orally administered with either vehicle or the compound (3
mg/kg, p.o.), and placed back in the locomotor chambers. After 60
minutes administration of the compound, the animals were taken out
again from the locomotor chambers, subcutaneously administrated
with vehicle (physiological saline) or MK-801 (0.3 mg/kg), and
placed back in the locomotor chambers. Locomotor activities were
counted every minute, and accumulated counts (120 minutes after
administration of MK-801) were calculated in each treatment group.
All data were shown as mean plus standard errors of the mean
(n=6-7) and analyzed using Welch's t-test for the control group and
the MK-801 single administration group (significant difference at
P<0.05), and Steel test for the comparison of the vehicle
administration group and the compound administration group
(significant difference at P<0.05). The results are shown in
FIG. 1.
The compounds in FIG. 1 correspond to the following Examples.
Compound A (Example 17)
Compound B (Example 21)
Compound C (Example 44)
Compound D (Example 52)
By oral administration 60 min before the treatment of MK-801 (0.3
mg/kg, s.c.); the compound showed a significant suppressive action
on the amount of MK-801 induced spontaneous locomotor
hyperactivity. **P<0.01 (comparison between control group and
MK-801 single administration group, Welch's t-test). #P<0.05
(comparison between vehicle administration group and compound
administration group, Steel test).
Formulation Example 1
TABLE-US-00024 (1) Compound of the Example 1 10.0 g (2) Lactose
70.0 g (3) Cornstarch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium
stearate 3.0 g
The compound of Example 16 (10.0 g) and magnesium stearate (3.0 g)
are granulated with an aqueous solution (70 ml) of soluble starch
(7.0 g as soluble starch), dried, and the resulting mixture is
mixed with lactose (70.0 g) and cornstarch (50.0 g) (lactose,
cornstarch, soluble starch and magnesium stearate are all products
on the Japanese Pharmacopoeia). The mixture is compressed to give
tablets.
INDUSTRIAL APPLICABILITY
The medicament of the present invention can be utilized as a
medicament for the prophylaxis or treatment of psychotic diseases
such as schizophrenia and the like, and the like.
This application is based on a patent application No. 2010-175374
filed in Japan, the contents of which are incorporated in full
herein.
Although the present invention have been presented or described by
referring to preferred embodiments of this invention, it will,
however, be understood by those of ordinary skill in the art that
various modifications may be made to the forms and details without
departing from the scope of the invention as set forth in the
appended claims.
* * * * *